Chemical compounds

ABSTRACT

and to pharmaceutically acceptable salts thereof, to processes and intermediates used for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of cell proliferative disorders.

This specification relates to certain indole compounds andpharmaceutically acceptable salts thereof that selectively down-regulatethe estrogen receptor and possess anti-cancer activity. Thisspecification also relates to use of said indole compounds andpharmaceutically acceptable salts thereof in methods of treatment of thehuman or animal body, for example in prevention or treatment of cancer.This specification also relates to processes and intermediate compoundsinvolved in the preparation of said indole compounds and topharmaceutical compositions containing them.

Estrogen receptor alpha (ERα, ESR1, NR3A) and estrogen receptor beta(ERβ, ESR2, NR3b) are steroid hormone receptors which are members of thelarge nuclear receptor family. Structured similarly to all nuclearreceptors, ERα is composed of six functional domains (named A-F)(Dahlman-Wright, et al., Pharmacol. Rev., 2006, 58:773-781) and isclassified as a ligand-dependent transcription factor because after itsassociation with the specific ligand, (the female sex steroid hormone17b estradiol (E2)), the complex binds to genomic sequences, namedEstrogen Receptor Elements (ERE) and interacts with co-regulators tomodulate the transcription of target genes. The ERα gene is located on6q25.1 and encodes a 595AA protein and multiple isoforms can be produceddue to alternative splicing and translational start sites. In additionto the DNA binding domain (Domain C) and the ligand binding domain(Domain E) the receptor contains a N-terminal (A/B) domain, a hinge (D)domain that links the C and E domains and a C-terminal extension (Fdomain). While the C and E domains of ERα and ERβ are quite conserved(96% and 55% amino acid identity respectively) conservation of the A/B,D and F domains is poor (below 30% amino acid identity). Both receptorsare involved in the regulation and development of the femalereproductive tract and in addition play roles in the central nervoussystem, cardiovascular system and in bone metabolism. The genomic actionof ERs occurs in the nucleus of the cell when the receptor binds EREsdirectly (direct activation or classical pathway) or indirectly(indirect activation or non-classical pathway). In the absence ofligand, ERs are associated with heat shock proteins, Hsp90 and Hsp70,and the associated chaperone machinery stabilizes the ligand bindingdomain (LBD) making it accessible to ligand. Liganded ER dissociatesfrom the heat shock proteins leading to a conformational change in thereceptor that allows dimerisation, DNA binding, interaction withco-activators or co-repressors and modulation of target gene expression.In the non-classical pathway, AP-1 and Sp-1 are alternative regulatoryDNA sequences used by both isoforms of the receptor to modulate geneexpression. In this example, ER does not interact directly with DNA butthrough associations with other DNA bound transcription factors e.g.c-Jun or c-Fos (Kushner et al., Pure Applied Chemistry 2003,75:1757-1769). The precise mechanism whereby ER affects genetranscription is poorly understood but appears to be mediated bynumerous nuclear factors that are recruited by the DNA bound receptor.The recruitment of co-regulators is primarily mediated by two proteinsurfaces, AF2 and AF1 which are located in E-domain and the A/B domainrespectively. AF1 is regulated by growth factors and its activitydepends on the cellular and promoter environment whereas AF2 is entirelydependent on ligand binding for activity. Although the two domains canact independently, maximal ER transcriptional activity is achievedthrough synergistic interactions via the two domains (Tzukerman, et al.,Mol. Endocrinology, 1994, 8:21-30). Although ERs are consideredtranscription factors they can also act through non-genomic mechanismsas evidenced by rapid ER effects in tissues following E2 administrationin a timescale that is considered too fast for a genomic action. It isstill unclear if receptors responsible for the rapid actions of estrogenare the same nuclear ERs or distinct G-protein coupled steroid receptors(Warner, et al., Steroids 2006 71:91-95) but an increasing number of E2induced pathways have been identified e.g. MAPK/ERK pathway andactivation of endothelial nitric oxide synthase and PI3K/Akt pathway. Inaddition to ligand dependent pathways, ERα has been shown to have ligandindependent activity through AF-1 which has been associated withstimulation of MAPK through growth factor signalling e.g. insulin likegrowth factor 1 (IGF-1) and epidermal growth factor (EGF). Activity ofAF-1 is dependent on phosphorylation of Ser118 and an example ofcross-talk between ER and growth factor signalling is thephosphorylation of Ser 118 by MAPK in response to growth factors such asIGF-1 and EGF (Kato, et al., Science, 1995, 270:1491-1494).

A large number of structurally distinct compounds have been shown tobind to ER. Some compounds such as endogenous ligand E2, act as receptoragonists whereas others competitively inhibit E2 binding and act asreceptor antagonists. These compounds can be divided into 2 classesdepending on their functional effects. Selective estrogen receptormodulators (SERMs) such as tamoxifen have the ability to act as bothreceptor agonists and antagonists depending on the cellular and promotercontext as well as the ER isoform targeted. For example tamoxifen actsas an antagonist in breast but acts as a partial agonist in bone, thecardiovascular system and uterus. All SERMs appear to act as AF2antagonists and derive their partial agonist characteristics throughAF1. A second group, fulvestrant being an example, are classified asfull antagonists and are capable of blocking estrogen activity via thecomplete inhibition of AF1 and AF2 domains through induction of a uniqueconformation change in the ligand binding domain (LBD) on compoundbinding which results in complete abrogation of the interaction betweenhelix 12 and the remainder of the LBD, blocking co-factor recruitment(Wakeling, et al., Cancer Res., 1991, 51:3867-3873; Pike, et al.,Structure, 2001, 9:145-153).

Intracellular levels of ERα are down-regulated in the presence of E2through the ubiquitin/proteasome (Ub/26S) pathway. Polyubiquitinylationof liganded ERα is catalysed by at least three enzymes; theubiquitin-activating enzyme E1 activated ubiquitin is conjugated by E2with lysine residues through an isopeptide bond by E3 ubiquitin ligaseand polyubiquitinated ERα is then directed to the proteasome fordegradation. Although ER-dependent transcription regulation andproteasome-mediated degradation of ER are linked (Lonard, et al., Mol.Cell, 2000 5:939-948), transcription in itself is not required for ERαdegradation and assembly of the transcription initiation complex issufficient to target ERα for nuclear proteasomal degradation. This E2induced degradation process is believed to necessary for its ability torapidly activate transcription in response to requirements for cellproliferation, differentiation and metabolism (Stenoien, et al., Mol.Cell Biol., 2001, 21:4404-4412). Fulvestrant is also classified as aselective estrogen receptor down-regulator (SERD), a subset ofantagonists that can also induce rapid down-regulation of ERα via the26S proteasomal pathway. In contrast a SERM such as tamoxifen canincrease ERα levels although the effect on transcription is similar tothat seen for a SERD.

Approximately 70% of breast cancers express ER and/or progesteronereceptors implying the hormone dependence of these tumour cells forgrowth. Other cancers such as ovarian and endometrial are also thoughtto be dependent on ERα signalling for growth. Therapies for suchpatients can inhibit ER signalling either by antagonising ligand bindingto ER e.g. tamoxifen which is used to treat early and advanced ERpositive breast cancer in both pre and post menopausal setting;antagonising and down-regulating ERα e.g. fulvestrant which is used totreat breast cancer in women which have progressed despite therapy withtamoxifen or aromatase inhibitors; or blocking estrogen synthesis e.g.aromatase inhibitors which are used to treat early and advanced ERpositive breast cancer. Although these therapies have had an enormouslypositive impact on breast cancer treatment, a considerable number ofpatients whose tumours express ER display de novo resistance to existingER therapies or develop resistance to these therapies over time. Severaldistinct mechanisms have been described to explain resistance tofirst-time tamoxifen therapy which mainly involve the switch fromtamoxifen acting as an antagonist to an agonist, either through thelower affinity of certain co-factors binding to the tamoxifen-ERαcomplex being off-set by over-expression of these co-factors, or throughthe formation of secondary sites that facilitate the interaction of thetamoxifen-ERα complex with co-factors that normally do not bind to thecomplex. Resistance could therefore arise as a result of the outgrowthof cells expressing specific co-factors that drive the tamoxifen-ERαactivity. There is also the possibility that other growth factorsignalling pathways directly activate the ER receptor or co-activatorsto drive cell proliferation independently of ligand signalling.

More recently, mutations in ESR1 have been identified as a possibleresistance mechanism in metastatic ER-positive patient derived tumoursamples and patient-derived xenograft models (PDX) at frequenciesvarying from 17-25%. These mutations are predominantly, but notexclusively, in the ligand-binding domain leading to mutated functionalproteins; examples of the amino acid changes include Ser463Pro,Val543Glu, Leu536Arg, Tyr537Ser, Tyr537Asn and Asp538Gly, with changesat amino acid 537 and 538 constituting the majority of the changescurrently described. These mutations have been undetected previously inthe genomes from primary breast samples characterised in the CancerGenome Atlas database. Of 390 primary breast cancer samples positive forER expression not a single mutation was detected in ESR1 (Cancer GenomeAtlas Network, 2012 Nature 490: 61-70). The ligand binding domainmutations are thought to have developed as a resistance response toaromatase inhibitor endocrine therapies as these mutant receptors showbasal transcriptional activity in the absence of estradiol. The crystalstructure of ER, mutated at amino acids 537 and 538, showed that bothmutants favoured the agonist conformation of ER by shifting the positionof helix 12 to allow co-activator recruitment and thereby mimickingagonist activated wild type ER. Published data has shown that endocrinetherapies such as tamoxifen and fulvestrant can still bind to ER mutantand inhibit transcriptional activation to some extent and thatfulvestrant is capable of degrading Try537Ser but that higher doses maybe needed for full receptor inhibition (Toy et al., Nat. Genetics 2013,45: 1439-1445; Robinson et al., Nat. Genetics 2013, 45: 144601451; Li,S. et al. Cell Rep. 4, 1116-1130 (2013). It is therefore feasible thatcertain compounds of the Formula (I) or pharmaceutically acceptablesalts thereof (as described hereinafter) will be capable ofdown-regulating and antagonising mutant ER although it is not known atthis stage whether ESR1 mutations are associated with an alteredclinical outcome.

Regardless of which resistance mechanism or combination of mechanismstakes place, many are still reliant on ER-dependent activities andremoval of the receptor through a SERD mechanism offers the best way ofremoving the ERα receptor from the cell. Fulvestrant is currently theonly SERD approved for clinical use, yet despite its mechanisticproperties, the pharmacological properties of the drug have limited itsefficacy due to the current limitation of a 500 mg monthly dose whichresults in less than 50% turnover of the receptor in patient samplescompared to the complete down-regulation of the receptor seen in invitro breast cell line experiments (Wardell, et al., Biochem. Pharm.,2011, 82:122-130). Hence there is a need for new ER targeting agentsthat have the required pharmaceutical properties and SERD mechanism toprovide enhanced benefit in the early, metastatic and acquiredresistance setting.

The compounds of the specification have been found to possess potentanti-tumour activity, being useful in inhibiting the uncontrolledcellular proliferation which arises from malignant disease. Thecompounds of the specification provide an anti-tumour effect by, as aminimum, acting as SERDs. For example, the compounds of thespecification may exhibit anti-tumour activity via the ability todown-regulate the estrogen receptor in a number of different breastcancer cell-lines, for example against the MCF-7, CAMA-1, BT474 and/orMDA-MB-134 breast cancer cell-lines. Such compounds may be expected tobe more suitable as therapeutic agents, particularly for the treatmentof cancer.

The compounds of the specification may also exhibit advantageousphysical properties (for example, lower lipophilicity, higher aqueoussolubility, higher permeability, lower plasma protein binding, and/orgreater chemical stability), and/or favourable toxicity profiles (forexample a decreased activity at hERG), and/or favourable metabolic orpharmacokinetic profiles, in comparison with other known SERDs. Suchcompounds may therefore be especially suitable as therapeutic agents,particularly for the treatment of cancer.

According to one aspect of the specification there is provided acompound of Formula (I):

wherein:

A is CR¹¹ or N; G is CR¹² or N; D is CR¹³ or N; E is CR¹⁴ or N; J isCR¹⁹ or N; Q is O, NH or NMe;

R¹ is CH₂F, CHF₂ or CF₃;R² is H, Me, CH₂F, CHF₂ or CF₃;

R³ is H or Me;

R⁴ is C₁₋₃ alkyl, CH₂F, CHF₂, CF₃, CH₂CH═CH₂, cyclopropyl or cyclobutyl;R⁵ is H, Me, CH₂F, CHF₂, CF₃, CN, CH₂CN, CH₂OMe, CH₂OH, COOH orCH₂SO₂Me;R⁶ is H, Me, F, CH₂F, CHF₂, CF₃, CN, CH₂CN, CH₂OMe, CH₂OH, COOH orSO₂Me;

R⁷ is H, Me or F; R⁸ is H, Me or F; or

R⁷ and R⁸ taken together with the carbon atom to which they are attachedform a cyclopropyl ring, a cyclobutyl ring, or an oxetane ring;R⁹ is H, Me, CH₂OH, CH₂OMe or F;R¹⁰ is H, Me, CH₂OH, CH₂OMe or F;R¹¹ is H, F, Cl, CN, C₁₋₃ alkyl or O—C₁₋₃ alkyl (wherein the said C₁₋₃alkyl groups are optionally substituted by a further group selected fromOMe, OH, F and CN);R¹² is H, F, Cl, CN, Me, OMe or CHF₂;

R¹³ is H, F, Cl, CN, Me or OMe; R¹⁴ is H, F, Cl, CN, Me or OMe; R¹⁵ isH, F, Cl or Me; R¹⁷ is H, F, Cl or Me; R¹⁸ is H, F, Cl or Me; R¹⁹ is Hor F; and R²⁰ is H or Me;

or a pharmaceutically acceptable salt thereof.

This specification also describes pharmaceutical compositions whichcomprise a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, in association with a pharmaceutically acceptableexcipient.

This specification also describes a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use as a medicament.

This specification also describes a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer.

This specification also describes combinations of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, with anotheranti-tumour agent, for use in the treatment of cancer.

Further aspects of the specification will be apparent to one skilled inthe art from reading this specification.

In one embodiment there is provided a compound of Formula (I) as definedabove.

In one embodiment there is provided a pharmaceutically acceptable saltof a compound of Formula (I).

In one embodiment D is CH.

In one embodiment E is CH.

In one embodiment both D and E are CH.

In one embodiment both D and E are N.

In one embodiment one of D or E is CH and the other of D or E is N.

In one embodiment A is CR¹¹.

In one embodiment G is CR¹².

In one embodiment A is CR¹¹ and G is CR¹².

In one embodiment A is CR¹¹ and G is CH.

In one embodiment A is CH and G is CR¹².

In one embodiment A is CR¹¹ and D, E and G are all CH;

In one embodiment R¹¹ is independently selected from Me, Cl, F or OMe.

In one embodiment R¹¹ is independently selected from H, F, CN or OMe.

In one embodiment R¹¹ is independently selected from H or OMe.

In one embodiment R¹¹ is independently selected from H or F.

In one embodiment R¹¹ is independently selected from F, Cl or OMe.

In one embodiment R¹¹ is H.

In one embodiment R¹¹ is OMe.

In one embodiment R¹¹ is F.

In one embodiment R¹¹ is Me.

In one embodiment R¹¹ is Cl.

In one embodiment R¹² is independently selected from Me, Cl, F or CHF₂.

In one embodiment R¹² is independently selected from H, F, CN or OMe.

In one embodiment R¹² is independently selected from H or OMe.

In one embodiment R¹² is independently selected from H or F.

In one embodiment R¹² is independently selected from H, Me or F.

In one embodiment R¹² is H.

In one embodiment R¹² is OMe.

In one embodiment R¹² is Me.

In one embodiment R¹² is F.

In one embodiment A is CR¹¹ and R¹¹ is H, F, CN or OMe.

In one embodiment G is CR¹² and R¹² is H, F, CN or OMe.

In one embodiment A is CR¹¹ and R¹¹ is Cl, F or OMe.

In one embodiment G is CR¹² and R¹² is H, Me or F.

In one embodiment A is CH and G is CH.

In one embodiment A is C—F and G is C—F.

In one embodiment A is C—F and G is CH.

In one embodiment A is C—OMe and G is CH.

In one embodiment A is CH and G is C—OMe.

In one embodiment A is C—F and G is C-Me.

In one embodiment A is C—Cl and G is C—F.

In one embodiment Q is O or NH.

In one embodiment Q is O.

In one embodiment Q is NH.

In one embodiment Q is NMe.

In one embodiment R¹ is CH₂F or CHF₂.

In one embodiment R¹ is CH₂F.

In one embodiment R¹ is CHF₂.

In one embodiment R¹ is CF₃.

In one embodiment R² is H or Me.

In one embodiment R² is H.

In one embodiment R² is Me.

In one embodiment R³ is H.

In one embodiment R³ is Me.

In one embodiment R⁴ is C₁₋₃ alkyl, CHF₂ or cyclopropyl.

In one embodiment R⁴ is C₁₋₃ alkyl or CHF₂.

In one embodiment R⁴ is C₁₋₃ alkyl, CF₃ or CHF₂.

In one embodiment R⁴ is C₁₋₃ alkyl.

In one embodiment R⁴ is Me.

In one embodiment R³ is H and R⁴ is Me.

In one embodiment R⁴ is CHF₂.

In one embodiment R⁴ is CF₃.

In one embodiment R⁵ is H or Me.

In one embodiment R⁵ is H.

In one embodiment R⁵ is Me.

In one embodiment R⁶ is H, Me, F, CH₂F, CH₂OMe, CH₂OH, COOH or SO₂Me.

In one embodiment R⁶ is H, F or CH₂OH.

In one embodiment R⁶ is F.

In one embodiment R⁶ is CH₂OH.

In one embodiment R⁶ is COOH.

In one embodiment R⁷ is H.

In one embodiment R⁷ is Me.

In one embodiment R⁷ is F.

In one embodiment R⁸ is Me or F.

In one embodiment R⁸ is Me.

In one embodiment R⁸ is F.

In one embodiment R⁸ is H.

In one embodiment R⁶ is F or CH₂OH and R⁷ is H.

In one embodiment R⁶ is F or CH₂OH and R⁷ is F.

In one embodiment R⁷ is H and R⁸ is F.

In one embodiment R⁷ is F and R⁸ is F.

In one embodiment R⁶ is F and R⁷ and R⁸ taken together with the carbonatom to which they are attached form a cyclopropyl ring, or a cyclobutylring, or an oxetane ring.

In one embodiment R⁶ is F and R⁷ and R⁸ taken together with the carbonatom to which they are attached form a cyclopropyl ring or an oxetanering.

In one embodiment R⁶ is F and R⁷ and R⁸ taken together with the carbonatom to which they are attached form a cyclopropyl ring.

In one embodiment R⁶ is F and R⁷ and R⁸ taken together with the carbonatom to which they are attached form a cyclobutyl ring.

In one embodiment R⁶ is F and R⁷ and R⁸ taken together with the carbonatom to which they are attached form an oxetane ring.

In one embodiment the group —CH(R⁵)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (I) is selected from the group consisting of:

In one embodiment the group —CH(R⁵)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (I) is selected from the group consisting of:

In one embodiment the group —CH(R⁵)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (I) is selected from the group consisting of:

In one embodiment the group —CH(R⁵)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (I) is selected from the group consisting of:

In one embodiment the group —CH(R⁵)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (I) is selected from the group consisting of:

In one embodiment the group —CH(R⁵)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (I) is selected from the group consisting of:

In one embodiment the group —CH(R⁵)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (I) is selected from the group consisting of:

In one embodiment the group —CH(R⁵)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (I) is selected from the group consisting of:

In one embodiment the group —CH(R⁵)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (I) is selected from the group consisting of:

In one embodiment the group —CH(R⁵)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (I) is selected from the group consisting of:

In one embodiment the group —CH(R⁵)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (I) is:

In one embodiment both R⁹ and R¹⁰ are H.

In one embodiment one of R⁹ and R¹⁰ is H, the other of R⁹ and R¹⁰ is Me,F, CH₂OH or CH₂OMe.

In one embodiment one of R⁹ and R¹⁰ is Me, the other of R⁹ and R¹⁰ is H.

In one embodiment J is N.

In one embodiment J is C—R¹⁹.

In one embodiment R¹⁵ is H, F or Me.

In one embodiment R¹⁵ is F.

In one embodiment R¹⁵ is H.

In one embodiment R¹⁷ is H or F.

In one embodiment R¹⁷ is F.

In one embodiment R¹⁷ is H.

In one embodiment R¹⁸ is H or F.

In one embodiment R¹⁸ is F.

In one embodiment R¹⁸ is H.

In one embodiment R¹⁹ is H or F.

In one embodiment R¹⁹ is F.

In one embodiment R¹⁹ is H.

In one embodiment, each of R¹⁷, R¹⁸ and R¹⁹ is H.

In one embodiment R²⁰ is H.

In one embodiment R²⁰ is Me.

In one embodiment there is provided a compound of Formula (I) wherein:

R², R³, R⁹, R¹⁰, R¹⁷ and R¹⁸ are each H;

R¹⁵ is H or F;

A is CR¹¹ and R¹¹ is H, F, CN or OMe;

G is CR¹² and R¹² is H, Me or F;

D is CH;

E is CH or N;

J is CH; and

the group —CH(R⁵)—C(R⁶)(R⁷)(R⁸) in the compound of Formula (I) isselected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In a further embodiment of the specification there is provided acompound of Formula (IA):

wherein:

A is CR¹ or N; G is CR¹² or N; D is CR¹³ or N; E is CR¹⁴ or N; J is CR¹⁹or N; Q is O, NH or NMe;

R¹ is CH₂F, CHF₂ or CF₃;R² is H, Me, CH₂F, CHF₂ or CF₃;

R³ is H or Me;

R⁴ is C₁₋₃ alkyl, CH₂F, CHF₂, CF₃, CH₂CH═CH₂, cyclopropyl or cyclobutyl;R⁵ is H, Me, CH₂F, CHF₂, CF₃, CN, CH₂CN, CH₂OMe, CH₂OH, COOH orCH₂SO₂Me;R⁶ is H, Me, F, CH₂F, CHF₂, CF₃, CN, CH₂CN, CH₂OMe, CH₂OH, COOH orSO₂Me;

R⁷ is H, Me or F; R⁸ is H, Me or F; or

R⁷ and R⁸ taken together with the carbon atom to which they are attachedform a cyclopropyl ring, a cyclobutyl ring, or an oxetane ring;R⁹ is H, Me, CH₂OH, CH₂OMe or F;R¹⁰ is H, Me, CH₂OH, CH₂OMe or F;R¹¹ is H, F, Cl, CN, C₁₋₃ alkyl or O—C₁₋₃ alkyl (wherein the said C₁₋₃alkyl groups are optionally substituted by a further group selected fromOMe, OH, F and CN);R¹² is H, F, Cl, CN, Me, OMe or CHF₂;

R¹³ is H, F, Cl, CN, Me or OMe; R¹⁴ is H, F, Cl, CN, Me or OMe; R¹⁵ isH, F, Cl or Me; R¹⁷ is H, F, Cl or Me; R¹⁸ is H, F, Cl or Me; and R¹⁹ isH or F;

or a pharmaceutically acceptable salt thereof.

In one embodiment D is CH.

In one embodiment E is CH.

In one embodiment both D and E are CH.

In one embodiment both D and E are N.

In one embodiment one of D or E is CH and the other of D or E is N.

In one embodiment A is CR¹¹.

In one embodiment G is CR¹².

In one embodiment A is CR¹¹ and G is CR¹².

In one embodiment A is CR¹¹ and G is CH.

In one embodiment A is CH and G is CR¹²

In one embodiment A is CR¹¹ and D, E and G are all CH;

In one embodiment R¹¹ is independently selected from Me, Cl, F or OMe.

In one embodiment R¹¹ is independently selected from H, F, CN or OMe.

In one embodiment R¹¹ is independently selected from H or OMe.

In one embodiment R¹¹ is independently selected from H or F.

In one embodiment R¹¹ is independently selected from F, Cl or OMe.

In one embodiment R¹¹ is H.

In one embodiment R¹¹ is OMe.

In one embodiment R¹¹ is F.

In one embodiment R¹¹ is Me.

In one embodiment R¹¹ is Cl.

In one embodiment R¹² is independently selected from Me, Cl, F or CHF₂.

In one embodiment R¹² is independently selected from H, F, CN or OMe.

In one embodiment R¹² is independently selected from H or OMe.

In one embodiment R¹² is independently selected from H or F.

In one embodiment R¹² is independently selected from H, Me or F.

In one embodiment R¹² is H.

In one embodiment R¹² is OMe.

In one embodiment R¹² is Me.

In one embodiment R¹² is F.

In one embodiment A is CR¹¹ and R¹¹ is H, F, CN or OMe.

In one embodiment G is CR¹² and R¹² is H, F, CN or OMe.

In one embodiment A is CR¹¹ and R¹¹ is Cl, F or OMe.

In one embodiment G is CR¹² and R¹² is H, Me or F.

In one embodiment A is CH and G is CH.

In one embodiment A is C—F and G is C—F.

In one embodiment A is C—F and G is CH.

In one embodiment A is C—OMe and G is CH.

In one embodiment A is CH and G is C—OMe.

In one embodiment A is C—F and G is C-Me.

In one embodiment A is C—Cl and G is C—F.

In one embodiment Q is O or NH.

In one embodiment Q is O.

In one embodiment Q is NH.

In one embodiment Q is NMe.

In one embodiment R¹ is CH₂F or CHF₂.

In one embodiment R¹ is CH₂F.

In one embodiment R¹ is CHF₂.

In one embodiment R¹ is CF₃.

In one embodiment R² is H or Me.

In one embodiment R² is H.

In one embodiment R² is Me.

In one embodiment R³ is H.

In one embodiment R³ is Me.

In one embodiment R⁴ is C₁₋₃ alkyl, CHF₂ or cyclopropyl.

In one embodiment R⁴ is C₁₋₃ alkyl or CHF₂.

In one embodiment R⁴ is C₁₋₃ alkyl, CF₃ or CHF₂.

In one embodiment R⁴ is C₁₋₃ alkyl.

In one embodiment R⁴ is Me.

In one embodiment R³ is H and R⁴ is Me.

In one embodiment R⁴ is CHF₂.

In one embodiment R⁴ is CF₃.

In one embodiment R⁵ is H or Me.

In one embodiment R⁵ is H.

In one embodiment R⁵ is Me.

In one embodiment R⁶ is H, Me, F, CH₂F, CH₂OMe, CH₂OH, COOH or SO₂Me.

In one embodiment R⁶ is H, F or CH₂OH.

In one embodiment R⁶ is F.

In one embodiment R⁶ is CH₂OH.

In one embodiment R⁶ is COOH.

In one embodiment R⁷ is H.

In one embodiment R⁷ is Me.

In one embodiment R⁷ is F.

In one embodiment R⁸ is Me or F.

In one embodiment R⁸ is Me.

In one embodiment R⁸ is F.

In one embodiment R⁸ is H.

In one embodiment R⁶ is F or CH₂OH and R⁷ is H.

In one embodiment R⁶ is F or CH₂OH and R⁷ is F.

In one embodiment R⁷ is H and R⁸ is F.

In one embodiment R⁷ is F and R⁸ is F.

In one embodiment R⁶ is F and R⁷ and R⁸ taken together with the carbonatom to which they are attached form a cyclopropyl ring, or a cyclobutylring, or an oxetane ring.

In one embodiment R⁶ is F and R⁷ and R⁸ taken together with the carbonatom to which they are attached form a cyclopropyl ring or an oxetanering.

In one embodiment R⁶ is F and R⁷ and R⁸ taken together with the carbonatom to which they are attached form a cyclopropyl ring.

In one embodiment R⁶ is F and R⁷ and R⁸ taken together with the carbonatom to which they are attached form a cyclobutyl ring.

In one embodiment R⁶ is F and R⁷ and R⁸ taken together with the carbonatom to which they are attached form an oxetane ring.

In one embodiment the group —CH(R⁵)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (IA) is selected from the group consisting of:

In one embodiment the group —CH(R⁵)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (IA) is selected from the group consisting of:

In one embodiment the group —CH(R⁵)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (IA) is selected from the group consisting of:

In one embodiment the group —CH(R)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (IA) is selected from the group consisting of:

In one embodiment the group —CH(R)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (IA) is selected from the group consisting of:

In one embodiment the group —CH(R⁵)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (IA) is selected from the group consisting of:

In one embodiment the group —CH(R⁵)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (IA) is selected from the group consisting of:

In one embodiment the group —CH(R)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (IA) is selected from the group consisting of:

In one embodiment the group —CH(R)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (IA) is selected from the group consisting of:

In one embodiment the group —CH(R⁵)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (IA) is:

In one embodiment both R⁹ and R¹⁰ are H.

In one embodiment one of R⁹ and R¹⁰ is H, the other of R⁹ and R¹⁰ is Me,F, CH₂OH or CH₂OMe.

In one embodiment one of R⁹ and R¹⁰ is Me, the other of R⁹ and R¹⁰ is H.

In one embodiment J is N.

In one embodiment J is C—R¹⁹.

In one embodiment R¹⁵ is H, F or Me.

In one embodiment R¹⁵ is F.

In one embodiment R¹⁵ is H.

In one embodiment R¹⁷ is H or F.

In one embodiment R¹⁷ is F.

In one embodiment R¹⁷ is H.

In one embodiment R¹⁸ is H or F.

In one embodiment R¹⁸ is F.

In one embodiment R¹⁸ is H.

In one embodiment R¹⁹ is H or F.

In one embodiment R¹⁹ is F.

In one embodiment R¹⁹ is H.

In one embodiment, each of R¹⁷, R¹⁸ and R¹⁹ is H.

In a further embodiment of the specification there is provided acompound of Formula (IB):

wherein:

A is CR₁₁ or N; G is CR₁₂ or N; D is CR₁₃ or N; E is CR¹⁴ or N; Q is O,NH or NMe;

R¹ is CH₂F, CHF₂ or CF₃;R² is H, Me, CH₂F, CHF₂ or CF₃;

R³ is H or Me;

R⁴ is C₁₋₃ alkyl, CH₂F, CHF₂, CF₃, CH₂CH═CH₂, cyclopropyl or cyclobutyl;R⁵ is H, Me, CH₂F, CHF₂, CF₃, CN, CH₂CN, CH₂OMe, CH₂OH, COOH orCH₂SO₂Me;R⁶ is H, Me, F, CH₂F, CHF₂, CF₃, CN, CH₂CN, CH₂OMe, CH₂OH, COOH orSO₂Me;

R⁷ is H, Me or F; R⁸ is H, Me or F; or

R⁷ and R⁸ taken together with the carbon atom to which they are attachedform a cyclopropyl ring or an oxetane ring;R⁹ is H, Me, CH₂OH, CH₂OMe or F;R¹⁰ is H, Me, CH₂OH, CH₂OMe or F;R¹¹ is H, F, Cl, CN, C₁₋₃ alkyl or O—C₁₋₃ alkyl (wherein the said C₁₋₃alkyl groups are optionally substituted by a further group selected fromOMe, OH, F and CN);

R¹² is H, F, Cl, CN, Me or OMe; R¹³ is H, F, Cl, CN, Me or OMe; R¹⁴ isH, F, Cl, CN, Me or OMe; and R¹⁵ is H or F;

or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided a compound of Formula (IC):

wherein:

Q is O, NH or NMe;

R¹ is CH₂F, CHF₂ or CF₃;R² is H, Me, CH₂F, CHF₂, or CF₃;

R³ is H or Me;

R⁴ is C₁₋₃ alkyl, CH₂F, CHF₂, CF₃, CH₂CH═CH₂, cyclopropyl or cyclobutyl;R⁵ is H, Me, CH₂F, CHF₂, CF₃, CN, CH₂CN, CH₂OMe, CH₂OH, COOH orCH₂SO₂Me;R⁶ is H, Me, F, CH₂F, CHF₂, CF₃, CN, CH₂CN, CH₂OMe, CH₂OH, COOH orSO₂Me;

R⁷ is H, Me or F; R⁸ is H, Me or F; or

R⁷ and R⁸ taken together with the carbon atom to which they are attachedform a cyclopropyl ring or an oxetane ring;R⁹ and R¹⁰ are each independently selected from H, Me, CH₂OH, CH₂OMe orF; andRing Y is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided a compound of Formula (IC), or apharmaceutically acceptable salt thereof, wherein Ring Y is selectedfrom the group consisting of:

In one embodiment there is provided a compound of Formula (IC), or apharmaceutically acceptable salt thereof, wherein Ring Y is selectedfrom the group consisting of:

In one embodiment there is provided a compound of Formula (IC), or apharmaceutically acceptable salt thereof, wherein Ring Y is selectedfrom the group consisting of:

In one embodiment there is provided a compound of Formula (IC), or apharmaceutically acceptable salt thereof, wherein Ring Y is selectedfrom the group consisting of:

In one embodiment there is provided a compound of Formula (IC), or apharmaceutically acceptable salt thereof, wherein Ring Y is selectedfrom the group consisting of:

In one embodiment there is provided a compound of Formula (IC), or a topharmaceutically acceptable salt thereof, wherein Q is NH.

In one embodiment there is provided a compound of Formula (IC), or apharmaceutically acceptable salt thereof, wherein Q is NMe.

In one embodiment there is provided a compound of Formula (IC), or apharmaceutically acceptable salt thereof, wherein Q is O.

In one embodiment there is provided a compound of Formula (IC), or apharmaceutically acceptable salt thereof, wherein R¹ is CH₂F.

In one embodiment there is provided a compound of Formula (IC), or apharmaceutically acceptable salt thereof, wherein R¹ is CHF₂.

In one embodiment there is provided a compound of Formula (IC), or apharmaceutically acceptable salt thereof, wherein R² is H.

In one embodiment there is provided a compound of Formula (IC), or apharmaceutically acceptable salt thereof, wherein R³ is H.

In one embodiment there is provided a compound of Formula (IC), or apharmaceutically acceptable salt thereof, wherein R⁴ is Me.

In one embodiment there is provided a compound of Formula (IC), or apharmaceutically acceptable salt thereof, wherein R³ is H and R⁴ is Me.

In one embodiment there is provided a compound of Formula (IC), or apharmaceutically acceptable salt thereof, wherein R⁵ is H.

In one embodiment there is provided a compound of Formula (IC), or apharmaceutically acceptable salt thereof, wherein R⁶ is H, F or CH₂OH.

In one embodiment there is provided a compound of Formula (IC), or apharmaceutically acceptable salt thereof, wherein R⁶ is F and R⁷ and R⁸taken together with the carbon atom to which they are attached form acyclopropyl ring, or a cyclobutyl ring, or an oxetane ring. In a furtherembodiment R⁷ and R⁸ taken together with the carbon atom to which theyare attached form a cyclopropyl ring. In a further embodiment R⁷ and R⁸taken together with the carbon atom to which they are attached form acyclobutyl ring. In a further embodiment R⁷ and R⁸ taken together withthe carbon atom to which they are attached form an oxetane ring.

In one embodiment there is provided a compound of Formula (IC), or apharmaceutically acceptable salt thereof, wherein both R⁹ and R¹⁰ are H.

In one embodiment the group —CH(R⁵)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (IC) is selected from the group consisting of:

In one embodiment the group —CH(R⁵)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (IC) is selected from the group consisting of:

In one embodiment the group —CH(R⁵)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (IC) is selected from the group consisting of:

In one embodiment the group —CH(R⁵)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (IC) is selected from the group consisting of:

In one embodiment the group —CH(R⁵)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (IC) is selected from the group consisting of:

In one embodiment the group —CH(R⁵)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (IC) is selected from the group consisting of:

In one embodiment the group —CH(R⁵)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (IC) is selected from the group consisting of:

In one embodiment the group —CH(R⁵)—C(R⁶)(R⁷)(R⁸) in the compound ofFormula (IC) is:

In one embodiment there is provided a compound of Formula (ID):

wherein:

Q is O, NH or NMe;

R¹ is CH₂F, CHF₂ or CF₃;

R₂ is H or Me: R³ is H or Me;

R⁴ is C₁₋₃ alkyl;

R⁹ is H or Me; R¹⁰ is H or Me;

R¹⁶ is selected from the group consisting of:

and Ring Y is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided a compound of Formula (ID), or apharmaceutically acceptable salt thereof, wherein Ring Y is selectedfrom the group consisting of:

In one embodiment there is provided a compound of Formula (ID), or apharmaceutically acceptable salt thereof, wherein Ring Y is selectedfrom the group consisting of:

In one embodiment there is provided a compound of Formula (ID), or apharmaceutically acceptable salt thereof, wherein Ring Y is selectedfrom the group consisting of:

In one embodiment there is provided a compound of Formula (ID), or apharmaceutically acceptable salt thereof, wherein Ring Y is selectedfrom the group consisting of:

In one embodiment there is provided a compound of Formula (ID), or apharmaceutically acceptable salt thereof, wherein Ring Y is selectedfrom the group consisting of:

In one embodiment there is provided a compound of Formula (ID), or apharmaceutically acceptable salt thereof, wherein Q is NH.

In one embodiment there is provided a compound of Formula (ID), or apharmaceutically acceptable salt thereof, wherein Q is NMe.

In one embodiment there is provided a compound of Formula (ID), or apharmaceutically acceptable salt thereof, wherein Q is O.

In one embodiment there is provided a compound of Formula (ID), or apharmaceutically acceptable salt thereof, wherein R¹ is CH₂F.

In one embodiment there is provided a compound of Formula (ID), or apharmaceutically acceptable salt thereof, wherein R¹ is CHF₂.

In one embodiment there is provided a compound of Formula (ID), or apharmaceutically acceptable salt thereof, wherein R² is H.

In one embodiment there is provided a compound of Formula (ID), or apharmaceutically acceptable salt thereof, wherein R³ is H.

In one embodiment there is provided a compound of Formula (ID), or apharmaceutically acceptable salt thereof, wherein R⁴ is Me.

In one embodiment the group R¹⁶ in the compound of Formula (ID) isselected from the group consisting of:

In one embodiment the group R¹⁶ in the compound of Formula (ID) isselected from the group consisting of:

In one embodiment the group R¹⁶ in the compound of Formula (ID) isselected from the group consisting of:

In one embodiment the group R¹⁶ in the compound of Formula (ID) isselected from the group consisting of:

In one embodiment the group R¹⁶ in the compound of Formula (ID) isselected from the group consisting of:

In one embodiment the group R¹⁶ in the compound of Formula (ID) isselected from the group consisting of:

In one embodiment the group R¹⁶ in the compound of Formula (ID) isselected from the group consisting of:

In one embodiment the group R¹⁶ in the compound of Formula (ID) is:

In one embodiment there is provided a compound of Formula (IE):

wherein:

Q is O, NH or NMe;

R¹ is CH₂F, CHF₂ or CF₃;

R² is H or Me; R³ is H or Me;

R⁴ is C₁₋₃ alkyl;

R⁹ is H or Me; R¹⁰ is H or Me;

R¹⁶ is selected from the group consisting of:

and Ring Y is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided a compound of Formula (IE), or apharmaceutically acceptable salt thereof, wherein Ring Y is selectedfrom the group consisting of:

In one embodiment there is provided a compound of Formula (IE), or apharmaceutically acceptable salt thereof, wherein Ring Y is selectedfrom the group consisting of:

In one embodiment there is provided a compound of Formula (IE), or apharmaceutically acceptable salt thereof, wherein Ring Y is selectedfrom the group consisting of:

In one embodiment there is provided a compound of Formula (IE), or apharmaceutically acceptable salt thereof, wherein Q is NH.

In one embodiment there is provided a compound of Formula (IE), or apharmaceutically acceptable salt thereof, wherein Q is NMe.

In one embodiment there is provided a compound of Formula (IE), or apharmaceutically acceptable salt thereof, wherein Q is O.

In one embodiment there is provided a compound of Formula (IE), or apharmaceutically acceptable salt thereof, wherein R¹ is CH₂F.

In one embodiment there is provided a compound of Formula (IE), or apharmaceutically acceptable salt thereof, wherein R¹ is CHF₂.

In one embodiment there is provided a compound of Formula (IE), or apharmaceutically acceptable salt thereof, wherein R² is H.

In one embodiment there is provided a compound of Formula (IE), or apharmaceutically acceptable salt thereof, wherein R³ is H.

In one embodiment there is provided a compound of Formula (IE), or apharmaceutically acceptable salt thereof, wherein R⁴ is Me.

In one embodiment the group R¹⁶ in the compound of Formula (IE) isselected from the group consisting of:

In one embodiment the group R¹⁶ in the compound of Formula (IE) isselected from the group consisting of:

In one embodiment the group R¹⁶ in the compound of Formula (IE) isselected from the group consisting of:

In one embodiment the group R¹⁶ in the compound of Formula (IE) isselected from the group consisting of:

In one embodiment the group R¹⁶ in the compound of Formula (IE) isselected from the group consisting of:

In one embodiment the group R¹⁶ in the compound of Formula (IE) isselected from the group consisting of:

In one embodiment there is provided a compound of Formula (IF):

wherein:

Q is O or NH; R¹⁵ is H or F;

R¹⁶ is selected from the group consisting of:

and Ring Y is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided a compound of Formula (IF), or apharmaceutically acceptable salt thereof, wherein Q is NH.

In one embodiment there is provided a compound of Formula (IF), or apharmaceutically acceptable salt thereof, wherein Q is O.

In one embodiment there is provided a compound of Formula (IF), or apharmaceutically acceptable salt thereof, wherein R¹⁵ is H;

In one embodiment there is provided a compound of Formula (IF), or apharmaceutically acceptable salt thereof, wherein R¹⁵ is F;

In one embodiment there is provided a compound of Formula (IF), or apharmaceutically acceptable salt thereof, wherein R¹⁶ is:

In one embodiment there is provided a compound of Formula (IF), or apharmaceutically acceptable salt thereof, wherein Ring Y is:

In one embodiment there is provided a compound of Formula (IF) wherein:

Q is O or NH; R¹⁵ is H or F;

R¹⁶ is selected from the group consisting of:

and Ring Y is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In a further embodiment, there is provided a compound of Formula (IG):

wherein:

A is CR¹¹ or N; G is CR¹²; D is CR¹³ or N; E is CR¹⁴ or N; J is CR¹⁹; Qis O or NH;

R¹ is CH₂F, CHF₂ or CF₃;R⁴ is Me, CHF₂ or CF₃;

R⁷ is H or Me; R⁸ is H or Me; or

R⁷ and R⁸ taken together with the carbon atom to which they are attachedform a cyclopropyl ring, or a cyclobutyl ring;

R¹¹ is H, Me, F, Cl or OMe;

R¹² is H, Me, F, Cl, or CHF₂;

R¹³ is H or F; R¹⁴ is H or F; R¹⁵ is H, F, or Me; R¹⁷ is H or F; R¹⁸ isH or F; and R¹⁹ is H or F;

or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided a compound of Formula (IG), or apharmaceutically acceptable salt thereof, wherein A is C—F, C—OMe orC—Cl.

In one embodiment there is provided a compound of Formula (IG), or apharmaceutically acceptable salt thereof, wherein G is C—H, C—F or C-Me.

In one embodiment there is provided a compound of Formula (IG), or apharmaceutically acceptable salt thereof, wherein D and E are both C—H.

In one embodiment there is provided a compound of Formula (IG), or apharmaceutically acceptable salt thereof, wherein D is C—H and E is N.

In one embodiment there is provided a compound of Formula (IG), or apharmaceutically acceptable salt thereof, wherein J is C—H.

In one embodiment there is provided a compound of Formula (IG), or apharmaceutically acceptable salt thereof, wherein R¹⁷ is H.

In one embodiment there is provided a compound of Formula (IG), or apharmaceutically acceptable salt thereof, wherein R¹⁸ is H.

In one embodiment there is provided a compound of Formula (IG), or apharmaceutically acceptable salt thereof, wherein R¹⁵ is H or F.

In one embodiment there is provided a compound of Formula (IG), or apharmaceutically acceptable salt thereof, wherein R¹ is CH₂F.

In one embodiment there is provided a compound of Formula (IG), or apharmaceutically acceptable salt thereof, wherein R⁴ is Me.

In one embodiment there is provided a compound of Formula (IG), or apharmaceutically acceptable salt thereof, wherein R⁷ is Me and R⁸ is H.

In one embodiment there is provided a compound of Formula (IG), or apharmaceutically acceptable salt thereof, wherein Q is O.

In one embodiment there is provided a compound of Formula (IG), or apharmaceutically acceptable salt thereof, wherein:

A is C—F, C—Cl or C—OMe; G is C—H, C-Me or C—F;

D and E are both C—H; or D is C—H and E is N;

J is C—H; Q is O;

R¹ is CH₂F;

R⁴ is Me; R⁷ is H; R⁸ is Me; R¹⁵ is H or F; and

R¹⁷ and R¹⁸ are both H.

According to a further embodiment of the specification there is provideda compound of Formula (IH):

wherein:

E is CH or N; Q is O, NH or NMe;

R¹ is CH₂F or CHF₂;

R³ is H or Me;

R⁴ is C₁₋₃ alkyl, CHF₂ or CF₃;

R⁷ is H, Me or F; R⁸ is H, Me or F; or

R⁷ and R⁸ taken together with the carbon atom to which they are attachedform a cyclobutyl ring;

R¹¹ is H, F, Cl, or OMe;

R¹² is H, F, Cl, CHF₂, or Me;

R¹⁵ is H or F; and R²⁰ is H or Me;

or a pharmaceutically acceptable salt thereof.

In a further embodiment, E in the compound of Formula (IH) is CH and R¹is CH₂F or CHF₂; or E in the compound of Formula (IH) is N and R¹ isCH₂F.

According to a further embodiment of the specification there is provideda compound of Formula (IJ):

wherein:

E is CH or N;

R¹ is CH₂F or CHF₂;

R¹⁵ is H or F; and R²⁰ is H or Me;

or a pharmaceutically acceptable salt thereof.

In a further embodiment, R¹⁵ in the compound of Formula (IJ) is H.

In a further embodiment, E in the compound of Formula (IJ) is N.

In a further embodiment, E in the compound of Formula (IJ) is CH and R¹is CH₂F or CHF₂; or E in the compound of Formula (IJ) is N and R¹ isCH₂F.

In a further embodiment, R¹ in the compound of Formula (IJ) is CH₂F.

In a further embodiment, R¹ in the compound of Formula (IJ) is CHF₂.

In a further aspect, there is provided a compound of Formula (IZ):

wherein:

A is CR¹¹ or N; G is CR¹² or N; D is CR¹³ or N; E is CR¹⁴ or N; Q is O,NH or NMe;

R¹ is CH₂F, CHF₂ or CF₃;R² is H, Me, CH₂F, CHF₂ or CF₃;

R³ is H or Me;

R⁴ is C₁₋₃ alkyl, CH₂F, CHF₂, CF₃, CH₂CH═CH₂, cyclopropyl or cyclobutyl;R⁵ is H, Me, CH₂F, CHF₂, CF₃, CN, CH₂CN, CH₂OMe, CH₂OH, COOH orCH₂SO₂Me;R⁶ is H, Me, F, CH₂F, CHF₂, CF₃, CN, CH₂CN, CH₂OMe, CH₂OH, COOH orSO₂Me;

R⁷ is H, Me or F; R⁸ is H, Me or F; or

R⁷ and R⁸ taken together with the carbon atom to which they are attachedform a cyclopropyl ring or an oxetane ring;R⁹ is H, Me, CH₂OH, CH₂OMe or F;R¹⁰ is H, Me, CH₂OH, CH₂OMe or F;R¹¹ is H, F, Cl, CN, C₁₋₃ alkyl or O—C₁₋₃ alkyl (wherein the said C₁₋₃alkyl groups are optionally substituted by a further group selected fromOMe, OH, F and CN);

R¹² is H, F, Cl, CN, Me or OMe; R¹³ is H, F, Cl, CN, Me or OMe; R¹⁴ isH, F, Cl, CN, Me or OMe; and R¹⁵ is H or F;

or a pharmaceutically acceptable salt thereof.

In a further aspect, there is provided a compound of Formula (IZA):

wherein:

A is CR¹¹ or N; G is CR¹² or N; D is CR¹³ or N; E is CR¹⁴ or N; Q is O,NH or NMe;

R¹ is CH₂F, CHF₂ or CF₃;R² is H, Me, CH₂F, CHF₂ or CF₃;

R³ is H or Me;

R⁴ is C₁₋₃ alkyl, CH₂F, CHF₂, CF₃, CH₂CH═CH₂, cyclopropyl or cyclobutyl;R⁵ is H, Me, CH₂F, CHF₂, CF₃, CN, CH₂CN, CH₂OMe, CH₂OH, COOH orCH₂SO₂Me;R⁶ is H, Me, F, CH₂F, CHF₂, CF₃, CN, CH₂CN, CH₂OMe, CH₂OH, COOH orSO₂Me;

R⁷ is H, Me or F; R⁸ is H, Me or F; or

R⁷ and R⁸ taken together with the carbon atom to which they are attachedform a cyclopropyl ring or an oxetane ring;R⁹ is H, Me, CH₂OH, CH₂OMe or F;R¹⁰ is H, Me, CH₂OH, CH₂OMe or F;R¹¹ is H, F, Cl, CN, C₁₋₃ alkyl or O—C₁₋₃ alkyl (wherein the said C₁₋₃alkyl groups are optionally substituted by a further group selected fromOMe, OH, F and CN);

R¹² is H, F, Cl, CN, Me or OMe; R¹³ is H, F, Cl, CN, Me or OMe; R¹⁴ isH, F, Cl, CN, Me or OMe; R¹⁵ is H or F; and R²⁰ is H or Me;

or a pharmaceutically acceptable salt thereof.

In a further embodiment there is provided the compound of Formula (IZ),(IZA), or a pharmaceutically acceptable salt thereof wherein thestereochemistry at the 1-position of thetetrahydro-1H-pyrido[3,4-b]indol-1-yl ring is S.

In a further embodiment there is provided the compound of Formula (IZ),(IZA), or a pharmaceutically acceptable salt thereof wherein thestereochemistry at the 1-position of thetetrahydro-1H-pyrido[3,4-b]indol-1-yl ring is R.

In a further embodiment there is provided the compound of Formula (IZ),(IZA), or a pharmaceutically acceptable salt thereof wherein thestereochemistry at the 3-position of thetetrahydro-1H-pyrido[3,4-b]indol-1-yl ring is S.

In a further embodiment there is provided the compound of Formula (IZ),(IZA), or a pharmaceutically acceptable salt thereof wherein thestereochemistry at the 3-position of thetetrahydro-1H-pyrido[3,4-b]indol-1-yl ring is R.

In one embodiment there is provided a compound of Formula (I), whereinthe compound is selected from the group consisting of:

-   3-Fluoro-N-(2-(3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine;-   N-1-(3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-N-2-(3-fluoropropyl)ethane-1,2-diamine;-   N-1-(3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-N-2-(3-fluoropropyl)-N-1-methylethane-1,2-diamine;-   3-Fluoro-N-(2-(3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-4-methoxyphenoxy)ethyl)propan-1-amine;-   3-fluoro-N-(2-(3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-2-methoxyphenoxy)ethyl)propan-1-amine;-   N-(2-(3-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-4-methoxyphenoxy)ethyl)-3-fluoropropan-1-amine;-   3-Fluoro-N-(2-(4-methoxy-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine;    and-   2,2-Difluoro-3-((1R,3R)-1-(5-(2-((3-fluoropropyl)amino)ethoxy)-2-methoxyphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propan-1-ol;    or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided a compound of Formula (I), whereinthe compound is selected from the group consisting of:

-   N-(2-(2,4-difluoro-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)-3-fluoropropan-1-amine;-   3-fluoro-N-(2-(4-fluoro-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine;-   3-fluoro-N-(2-(2-fluoro-4-methoxy-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine;-   3-fluoro-N-(2-((5-methoxy-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-2-yl)oxy)ethyl)propan-1-amine;-   N-(2-(2,4-difluoro-3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)-3-fluoropropan-1-amine;-   3-((1R,3R)-1-(2,6-difluoro-3-(2-((3-fluoropropyl)amino)ethoxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;-   3-((1R,3R)-1-(2,6-difluoro-3-(2-((3-fluoropropyl)amino)ethoxy)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;-   3-fluoro-N-(2-(3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine;-   3-fluoro-N-(2-(4-methyl-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine;-   3-fluoro-N-(2-(3-methyl-5-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine;-   3-fluoro-N-(2-(2-methyl-5-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine;-   3-fluoro-N-(2-(2-methyl-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine;-   N-(2-(4-ethyl-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)-3-fluoropropan-1-amine;-   N-(2-(4-chloro-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)-3-fluoropropan-1-amine;-   4-(2-((3-fluoropropyl)amino)ethoxy)-2-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)benzonitrile;-   3-fluoro-N-(2-(2-fluoro-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine;-   N-(2-(2-chloro-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)-3-fluoropropan-1-amine;-   3-fluoro-N-(2-(4-methoxy-2-methyl-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine;-   3-fluoro-N-(2-(3-fluoro-4-methoxy-5-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine;-   3-fluoro-N-(2-(2-fluoro-4-methoxy-5-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine;-   N-(2-(2,5-difluoro-4-methoxy-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)-3-fluoropropan-1-amine;-   N-(2-(3,4-difluoro-5-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)-3-fluoropropan-1-amine;-   N-(2-(2,5-difluoro-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)-3-fluoropropan-1-amine;-   3-fluoro-N-(2-(2,4,5-trifluoro-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine;-   3-fluoro-N-(2-(4-fluoro-2-methyl-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine;-   3-fluoro-N-(2-((6-((1 S,    3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-2-yl)oxy)ethyl)propan-1-amine;-   3-fluoro-N-(2-((2-((1 S,    3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-4-yl)oxy)ethyl)propan-1-amine;-   3-fluoro-N-(2-((6-methoxy-5-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-3-yl)oxy)ethyl)propan-1-amine;-   3-fluoro-N-(2-((6-methyl-5-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-3-yl)oxy)ethyl)propan-1-amine;-   3-fluoro-N-(2-((4-methyl-5-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-3-yl)oxy)ethyl)propan-1-amine;-   3-fluoro-N-(2-((5-fluoro-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-2-yl)oxy)ethyl)propan-1-amine;-   N1-(3-fluoropropyl)-N2-(4-methoxy-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)ethane-1,2-diamine;-   N1-(3-fluoropropyl)-N2-(6-methoxy-5-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-3-yl)ethane-1,2-diamine;-   N1-(3-fluoropropyl)-N2-(5-methoxy-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-2-yl)ethane-1,2-diamine;-   N1-(3-fluoropropyl)-N2-(5-methoxy-6-((1 S,    3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-2-yl)ethane-1,2-diamine;-   3-((1R,3R)-1-(2-chloro-5-(2-((3-fluoropropyl)amino)ethoxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;-   2,2-difluoro-3-((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propan-1-ol;-   2,2-difluoro-3-((1R,3R)-6-fluoro-1-(5-(2-((3-fluoropropyl)amino)ethoxy)-2-methoxyphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propan-1-ol;-   2,2-difluoro-3-((1R,3R)-1-(5-(((R)-1-((3-fluoropropyl)amino)propan-2-yl)oxy)-2-methoxyphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propan-1-ol;-   2,2-difluoro-3-((1R,3R)-1-(5-(((S)-1-((3-fluoropropyl)amino)propan-2-yl)oxy)-2-methoxyphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propan-1-ol;-   2,2-difluoro-3-((1R,3R)-1-(5-((S)-2-((3-fluoropropyl)amino)propoxy)-2-methoxyphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propan-1-ol;-   2,2-difluoro-3-((1R,3R)-1-(5-((R)-2-((3-fluoropropyl)amino)propoxy)-2-methoxyphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propan-1-ol;-   N-(2-(3-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-2,4-difluorophenoxy)ethyl)-3-fluoropropan-1-amine;-   3-fluoro-N-(2-(3-((1R,3R)-2-((1-fluorocyclopropyl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-4-methoxyphenoxy)ethyl)propan-1-amine;-   (S)-3-((1R,3R)-1-(5-(2-((3-fluoropropyl)amino)ethoxy)-2-methoxyphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (S)-3-((1R,3R)-1-(6-chloro-2-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (S)-3-((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid; and-   3-fluoro-N-(2-((5-methoxy-6-((1S,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-2-yl)oxy)ethyl)propan-1-amine;    or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided a compound of Formula (I), whereinthe compound is selected from the group consisting of:

-   (S)-3-((1R,3R)-1-(2,6-difluoro-3-(2-((3-fluoropropyl)amino)ethoxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (S)-3-((1R,3R)-1-(2,6-difluoro-3-(2-((3-fluoropropyl)amino)ethoxy)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   3-((1R,3R)-1-(2,6-difluoro-3-(2-((3-fluoropropyl)amino)ethoxy)phenyl)-8-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;-   3-((1R,3R)-1-(2,6-difluoro-3-(2-((3-fluoropropyl)amino)ethoxy)phenyl)-7-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;-   3-((1R,3R)-1-(2,6-difluoro-3-(2-((3-fluoropropyl)amino)ethoxy)phenyl)-5-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;-   3-((1R,3R)-1-(2,6-difluoro-3-(2-((3-fluoropropyl)amino)ethoxy)phenyl)-3,6-dimethyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;-   3-((1R,3R)-1-(3,5-difluoro-2-(2-((3-fluoropropyl)amino)ethoxy)pyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;-   3-((1R,3R)-1-(3,5-difluoro-2-(2-((3-fluoropropyl)amino)ethoxy)pyridin-4-yl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;-   3-((1R,3R)-1-(3,5-difluoro-2-(2-((3-fluoropropyl)amino)ethoxy)pyridin-4-yl)-3,6-dimethyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;-   3-((1R,3R)-1-(3,5-difluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)pyridin-4-yl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;-   3-((1R,3R)-1-(2-(difluoromethyl)-3-(2-((3-fluoropropyl)amino)ethoxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;-   2-(2-((3-fluoropropyl)amino)ethoxy)-6-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)benzonitrile;-   (4-(2-((3-fluoropropyl)amino)ethoxy)-2-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)methanol;-   3-fluoro-N-(2-(4-(methoxymethyl)-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine;-   3,3,3-trifluoro-N-(2-(4-methoxy-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine;-   3-fluoro-N-(2-(3-fluoro-5-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine;-   3-fluoro-N-(2-(2-fluoro-5-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine;-   N-(2-(3-((1R,3R)-1,3-dimethyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)-3-fluoropropan-1-amine;-   N-(2-(2,4-difluoro-3-((1R,3R)-2-((1-fluorocyclopropyl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)-3-fluoropropan-1-amine;-   N-(2-(2,4-difluoro-3-((1R,3R)-3-methyl-2-((1-(methylsulfonyl)cyclopropyl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)-3-fluoropropan-1-amine;-   N-(2-(4-chloro-2-fluoro-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)-3-fluoropropan-1-amine;-   N-(2-(2,4-dimethyl-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)-3-fluoropropan-1-amine;-   3-fluoro-N-(2-(2-fluoro-4-methyl-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine;-   2,2-difluoro-3-((1R,3R)-1-(2-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-6-methoxyphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propan-1-ol;-   N-(2-(3-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-2-fluoro-4-methoxyphenoxy)ethyl)-3-fluoropropan-1-amine;-   3-fluoro-N-(2-(2-fluoro-3-((1R,3R)-2-((1-fluorocyclopropyl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-4-methoxyphenoxy)ethyl)propan-1-amine;-   3-fluoro-N-(2-(2-fluoro-3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-4-methoxyphenoxy)ethyl)propan-1-amine;-   3-((1R,3R)-1-(2-chloro-6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;-   2,2-difluoro-3-((1R,3R)-6-fluoro-1-(2-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-6-methoxyphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propan-1-ol;-   3-((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propanenitrile;-   N1-(2,4-difluoro-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-ol-yl)phenyl)-N2-(3-fluoropropyl)ethane-1,2-diamine;-   3-((1R,3R)-1-(2,6-difluoro-3-((2-((3-fluoropropyl)amino)ethyl)amino)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;-   N1-(2-fluoro-4-methoxy-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-N2-(3-fluoropropyl)ethane-1,2-diamine;-   N1-(2-fluoro-4-methoxy-5-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-N2-(3-fluoropropyl)ethane-1,2-diamine;-   3-fluoro-N-(2-((3-fluoro-2-((1S,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-4-yl)oxy)ethyl)propan-1-amine;-   N-(2-((3-chloro-2-((1S,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-4-yl)oxy)ethyl)-3-fluoropropan-1-amine;-   N1-(3-fluoro-2-((1S,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-4-yl)-N2-(3-fluoropropyl)ethane-1,2-diamine;-   N1-(3-fluoropropyl)-N2-(3-methyl-2-((1S,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-4-yl)ethane-1,2-diamine;-   2,2-difluoro-3-((1S,3R)-1-(4-(2-((3-fluoropropyl)amino)ethoxy)-3-methylpyridin-2-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propan-1-ol;-   2,2-difluoro-3-((1S,3R)-1-(3-fluoro-4-(2-((3-fluoropropyl)amino)ethoxy)pyridin-2-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propan-1-ol;-   N-(2-((2-((1S,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3-fluoropyridin-4-yl)oxy)ethyl)-3-fluoropropan-1-amine;-   3-fluoro-N-(2-((3-fluoro-2-((1S,3R)-2-((1-fluorocyclopropyl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-4-yl)oxy)ethyl)propan-1-amine;-   3-fluoro-N-(2-((3-fluoro-2-((1S,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-4-yl)oxy)ethyl)propan-1-amine;-   3-fluoro-N-(2-((5-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1    l-yl)pyridin-3-yl)oxy)ethyl)propan-1-amine;-   3-fluoro-N-(2-((4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-2-yl)oxy)ethyl)propan-1-amine;-   2,2-difluoro-3-((1R,3R)-1-(2-(2-((3-fluoropropyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propan-1-ol;-   3-((1R,3R)-1-(3-chloro-2-(2-((3-fluoropropyl)amino)ethoxy)pyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;-   3-fluoro-N-(2-((5-methyl-6-((1S,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-2-yl)oxy)ethyl)propan-1-amine;-   3-fluoro-N-(2-((3-methyl-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-2-yl)oxy)ethyl)propan-1-amine;-   N-(2-((3,5-difluoro-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-2-yl)oxy)ethyl)-3-fluoropropan-1-amine;-   N-(2-((3,5-difluoro-4-((1R,3R)-2-((1-fluorocyclopropyl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-2-yl)oxy)ethyl)-3-fluoropropan-1-amine;-   N-(2-((3,5-difluoro-4-((1R,3R)-6-fluoro-2-((1-fluorocyclopropyl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-2-yl)oxy)ethyl)-3-fluoropropan-1-amine;-   2,2-difluoro-3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propan-1-ol;-   3-((1R,3R)-1-(3-chloro-5-fluoro-2-(2-((3-fluoropropyl)amino)ethoxy)pyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;-   3-fluoro-N-(2-((6-methoxy-5-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridazin-3-yl)oxy)ethyl)propan-1-amine;-   3-fluoro-N-(2-((6-((1 S,    3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyrimidin-4-yl)oxy)ethyl)propan-1-amine;-   3-fluoro-N-(2-((5-methyl-6-((1S,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyrimidin-4-yl)oxy)ethyl)propan-1-amine;-   2,2-difluoro-3-((1S,3R)-1-(6-(2-((3-fluoropropyl)amino)ethoxy)-5-methylpyrimidin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propan-1-ol;-   3-((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propanoic    acid;-   (R)-3-((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   2,2-difluoro-3-((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propanoic    acid;-   3-((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-dimethylpropanoic    acid;-   1-(((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)methyl)cyclobutane-1-carboxylic    acid;-   (R)-3-((1R,3R)-6-fluoro-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (S)-3-((1R,3R)-3-ethyl-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (R)-3-((1R,3R)-1-(3-(2-((3,3-difluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (S)-3-((1R,3R)-1-(3-(2-((3,3-difluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (S)-3-((1R,3R)-1-(2-(difluoromethyl)-6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (S)-3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (R)-3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (S)-3-((1R,3R)-1-(2,6-dichloro-3-(2-((3-fluoropropyl)amino)ethoxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (S)-3-((1R,3R)-1-(2,6-dichloro-3-(2-((3-fluoropropyl)amino)ethoxy)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (R)-3-((1R,3R)-1-(2,6-dichloro-3-(2-((3-fluoropropyl)amino)ethoxy)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   3-((1R,3R)-1-(2-chloro-6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-((1R,3R)-1-(2-(2-((3-fluoropropyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (S)-3-((1R,3R)-1-(3-chloro-5-fluoro-2-(2-((3-fluoropropyl)amino)ethoxy)pyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (S)-3-((R)-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-3,3-dimethyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (S)-3-((1R,3R)-1-(6-fluoro-3-((2-((3-fluoropropyl)amino)ethyl)amino)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (S)-3-((1R,3R)-1-(6-fluoro-3-((2-((3-fluoropropyl)amino)ethyl)(methyl)amino)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (S)-3-((1R,3S)-3-(difluoromethyl)-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (S)-3-((1R,3S)-1-(2-chloro-6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)phenyl)-3-(difluoromethyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (S)-3-((1R,3S)-1-(3-chloro-5-fluoro-2-(2-((3-fluoropropyl)amino)ethoxy)pyridin-4-yl)-3-(difluoromethyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (S)-3-((1R,3    S)-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-3-(trifluoromethyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (S)-3-((1R,3S)-1-(2-chloro-6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)phenyl)-3-(trifluoromethyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (S)-3-((1R,3S)-1-(3-chloro-5-fluoro-2-(2-((3-fluoropropyl)amino)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (S)-3-((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (S)-3-((1R,3R)-1-(2,6-difluoro-3-(2-((3-fluoropropyl)(methyl)amino)ethoxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (S)-3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   is    (S)-3-((1R,3R)-6-fluoro-1-(6-fluoro-3-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (S)-3-((1R,3R)-1-(6-fluoro-3-((2-((3-fluoropropyl)(methyl)amino)ethyl)(methyl)amino)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (S)-3-((1R,3R)-1-(2-(difluoromethyl)-6-fluoro-3-(2-((3-fluoropropyl)(methyl)amino)ethoxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (S)-3-((1R,3S)-1-(6-fluoro-3-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-2-methylphenyl)-3-(trifluoromethyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (S)-3-((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)(methyl-d3)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (R)-3-((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (R)-3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (R)-3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl-d3)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid; and-   N-(2-(2,4-difluoro-3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)-3-fluoro-N-methylpropan-1-amine;    or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided a compound of Formula (I), whereinthe compound is selected from the group consisting of:

-   (2R)-3-[(1R,3R)-6-fluoro-1-[5-fluoro-2-[2-[3-fluoropropyl(methyl)amino]ethoxy]-3-methyl-4-pyridyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-methyl-propanoic    acid;-   3-((1R,3R)-6-fluoro-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propanoic    acid;-   3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propanoic    acid;-   3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butanoic    acid;-   (3R)-3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)    ethoxy)-3-methyl    pyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butanoic    acid;-   (3S)-3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)    ethoxy)-3-methyl    pyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butanoic    acid;-   (R)-3-((1R,3R)-6-fluoro-1-(6-fluoro-3-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (R)-3-((1R,3R)-1-(2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid;-   (R)-3-((1R,3R)-1-(3-(2-((3,3-difluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoic    acid; and-   3-((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propanoic    acid;

or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided a compound of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or apharmaceutically acceptable salt thereof, wherein the compound isselected from any of the Examples in the specification. A furtherfeature is any of the embodiments described in the specification withthe proviso that any of the specific Examples are individuallydisclaimed. A further feature is any of the embodiments described in thespecification with the proviso that any one or more of the compoundsselected from the above list of examples of compounds of thespecification are individually disclaimed.

The C₁₋₃ alkyl group may be branched or unbranched. Examples of suitableC₁₋₃ alkyl groups are methyl (Me), ethyl (Et), n-propyl (n-Pr) ori-propyl (i-Pr).

For the avoidance of doubt, in the compound of Formula (I), (IA), (IB),(IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), the substituents R⁹and R¹⁰ may each be substituted at either position of the respectiveethyl chain with which they are associated. Therefore, by way of exampleonly, the R⁹ substituent may be attached in the two possible positionsas shown below:

For the further avoidance of doubt, the use of

in formulae of this specification denotes the point of attachmentbetween different groups.

For the further avoidance of doubt, where multiple substituents areindependently selected from a given group, the selected substituents maycomprise the same substituents or different substituents from within thegiven group.

The compounds of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH),(IJ), (IZ), or (IZA), have two or more chiral centres and it will berecognised that the compounds of Formula (I), (IA), (IB), (IC), (ID),(IE), (IF), (IH), (IJ), (IZ), or (IZA), may be prepared, isolated and/orsupplied with or without the presence, in addition, of one or more ofthe other possible enantiomeric and/or diastereomeric isomers of thecompounds of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH),(IJ), (IZ), or (IZA), in any relative proportions. The preparation ofenantioenriched/enantiopure and/or diastereoenriched/diastereopurecompounds may be carried out by standard techniques of organic chemistrythat are well known in the art, for example by synthesis fromenantioenriched or enantiopure starting materials, use of an appropriateenantioenriched or enantiopure catalyst during synthesis, and/or byresolution of a racemic or partially enriched mixture of stereoisomers,for example via chiral chromatography.

For use in a pharmaceutical context it may be preferable to provide acompound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ),(IZ), or (IZA), or a pharmaceutically acceptable salt thereof withoutlarge amounts of the other stereoisomeric forms being present.

Accordingly, in one embodiment there is provided a compositioncomprising a compound of Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable saltthereof, optionally together with one or more of the otherstereoisomeric forms of the compound of Formula (I), (IA), (IB), (IC),(ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or pharmaceuticallyacceptable salt thereof, wherein the compound of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), orpharmaceutically acceptable salt thereof is present within thecomposition with a diastereomeric excess (% de) of ≥90%.

In a further embodiment the % de in the above-mentioned composition is≥95%.

In a further embodiment the % de in the above-mentioned composition is≥98%.

In a further embodiment the % de in the above-mentioned composition is≥99%.

In a further embodiment there is provided a composition comprising acompound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ),(IZ), or (IZA), or a pharmaceutically acceptable salt thereof,optionally together with one or more of the other stereoisomeric formsof the compound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF),(IH), (IJ), (IZ), or (IZA), or pharmaceutically acceptable salt thereof,wherein the compound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF),(IH), (IJ), (IZ), or (IZA), or pharmaceutically acceptable salt thereofis present within the composition with an enantiomeric excess (% ee) of≥90%.

In a further embodiment the % ee in the above-mentioned composition is≥95%.

In a further embodiment the % ee in the above-mentioned composition is≥98%.

In a further embodiment the % ee in the above-mentioned composition is≥99%.

In a further embodiment there is provided a composition comprising acompound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ),(IZ), or (IZA), or a pharmaceutically acceptable salt thereof,optionally together with one or more of the other stereoisomeric formsof the compound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF),(IH), (IJ), (IZ), or (IZA), or pharmaceutically acceptable salt thereof,wherein the compound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF),(IH), (IJ), (IZ), or (IZA), or pharmaceutically acceptable salt thereofis present within the composition with an enantiomeric excess (% ee) of≥90% and a diastereomeric excess (% de) of ≥90%.

In further embodiments of the above-mentioned composition the % ee and %de may take any combination of values as listed below:

-   -   The % ee is ≤5% and the % de is ≥80%.    -   The % ee is ≤5% and the % de is ≥90%.    -   The % ee is ≤5% and the % de is ≥95%.    -   The % ee is ≤5% and the % de is ≥98%.    -   The % ee is ≥95% and the % de is ≥95%.    -   The % ee is ≥98% and the % de is ≥98%.    -   The % ee is ≥99% and the % de is ≥99%.

In a further embodiment there is provided a pharmaceutical compositionwhich comprises a compound of the Formula (I), (IA), (IB), (IC), (ID),(IE), (IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptablesalt thereof, in association with a pharmaceutically acceptableexcipient.

In one embodiment there is provided a pharmaceutical composition whichcomprises a compound of the Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable saltthereof, in association with a pharmaceutically acceptable excipient,optionally further comprising one or more of the other stereoisomericforms of the compound of Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), or to pharmaceutically acceptable saltthereof, wherein the compound of Formula (I), (IA), (IB), (IC), (ID),(IE), (IF), (IH), (IJ), (IZ), or (IZA), or pharmaceutically acceptablesalt thereof is present within the composition with an enantiomericexcess (% ee) of ≥90%.

In a further embodiment the % ee in the above-mentioned composition is≥95%.

In a further embodiment the % ee in the above-mentioned composition is≥98%.

In a further embodiment the % ee in the above-mentioned composition is≥99%.

In one embodiment there is provided a pharmaceutical composition whichcomprises a compound of the Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable saltthereof, in association with a pharmaceutically acceptable excipient,optionally further comprising one or more of the other stereoisomericforms of the compound of Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), or pharmaceutically acceptable saltthereof, wherein the compound of Formula (I), (IA), (IB), (IC), (ID),(IE), (IF), (IH), (IJ), (IZ), or (IZA), or pharmaceutically acceptablesalt thereof is present within the composition with a diastereomericexcess (% de) of ≥90%.

In a further embodiment the % de in the above-mentioned composition is≥95%.

In a further embodiment the % de in the above-mentioned composition is≥98%.

In a further embodiment the % de in the above-mentioned composition is≥99%.

In one embodiment there is provided a pharmaceutical composition whichcomprises a compound of the Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable saltthereof, in association with a pharmaceutically acceptable excipient,optionally further comprising one or more of the other stereoisomericforms of the compound of Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), or pharmaceutically acceptable saltthereof, wherein the compound of Formula (I), (IA), (IB), (IC), (ID),(IE), (IF), (IH), (IJ), (IZ), or (IZA), or pharmaceutically acceptablesalt thereof is present within the composition with an enantiomericexcess (% ee) of ≥90% and a diastereomeric excess (% de) of ≥90%.

In further embodiments of the above-mentioned pharmaceutical compositionthe % ee and % de may take any combination of values as listed below:

-   -   The % ee is ≥95% and the % de is ≥95%.    -   The % ee is ≥98% and the % de is ≥98%.    -   The % ee is ≥99% and the % de is ≥99%.

The compounds of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH),(IJ), (IZ), or (IZA), and pharmaceutically acceptable salts thereof maybe prepared, used or supplied in amorphous form, crystalline form, orsemicrystalline form and any given compound of Formula (I), (IA), (IB),(IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or pharmaceuticallyacceptable salt thereof may be capable of being formed into more thanone crystalline/polymorphic form, including hydrated (e.g. hemi-hydrate,a mono-hydrate, a di-hydrate, a tri-hydrate or other stoichiometry ofhydrate) and/or solvated forms. It is to be understood that the presentspecification encompasses any and all such solid forms of the compoundof Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or(IZA), and pharmaceutically acceptable salts thereof.

In further embodiments there is provided a compound of Formula (I),(IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), which isobtainable by the methods described in the ‘Examples’ sectionhereinafter.

The present specification is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes will be understood toinclude those atoms having the same atomic number but different massnumbers. For example, isotopes of hydrogen include tritium anddeuterium. Isotopes of carbon include ¹³C and ¹⁴C. Isotopes of nitrogeninclude ¹⁵N. In a particular embodiment there is provided a compound ofFormula (I), (IA), (IB), (IC), (ID), (IE), (IZ), or (IZA), wherein R² isdeuterium. In a further embodiment there is provided a compound ofFormula (I), (IH), (IJ) or (IZA) where R²⁰ is CD₃.

A suitable pharmaceutically acceptable salt of a compound of the Formula(I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), is,for example, an acid addition salt. A suitable pharmaceuticallyacceptable salt of a compound of Formula (I), (IA), (IB), (IC), (ID),(IE), (IF), (IH), (IJ), (IZ), or (IZA), may be, for example, anacid-addition salt of a compound of the Formula (I), (IA), (IB), (IC),(ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), for example anacid-addition salt with an inorganic or organic acid such as aceticacid, adipic acid, benzene sulfonic acid, benzoic acid, cinnamic acid,citric acid, D,L-lactic acid, ethane disulfonic acid, ethane sulfonicacid, fumaric acid, hydrochloric acid, L-tartaric acid, maleic acid,malic acid, malonic acid, methane sulfonic acid, napadisylic acid,phosphoric acid, saccharin, succinic acid, sulfuric acid,p-toluenesulfonic acid, toluene sulfonic acid or trifluoroacetic acid.

A further suitable pharmaceutically acceptable salt of a compound of theFormula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or(IZA), is, for example, a salt formed within the human or animal bodyafter administration of a compound of the Formula (I), (IA), (IB), (IC),(ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), to said human or animalbody.

The compound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH),(IJ), (IZ), or (IZA), or pharmaceutically acceptable salt thereof may beprepared as a co-crystal solid form. It is to be understood that apharmaceutically acceptable co-crystal of a compound of the Formula (I),(IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), orpharmaceutically acceptable salts thereof, form an aspect of the presentspecification.

It is to be understood that a suitable pharmaceutically acceptablepro-drug of a compound of the Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), also forms an aspect of the presentspecification. Accordingly, the compounds of the specification may beadministered in the form of a pro-drug, which is a compound that isbroken down in the human or animal body to release a compound of thespecification. A pro-drug may be used to alter the physical propertiesand/or the pharmacokinetic properties of a compound of thespecification. A pro-drug can be formed when the compound of thespecification contains a suitable group or substituent to which aproperty-modifying group can be attached. Examples of pro-drugs includein-vivo cleavable ester or amide derivatives of the compound of theFormula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or(IZA).

Accordingly, one aspect of the present specification includes thosecompounds of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH),(IJ), (IZ), or (IZA), as defined hereinbefore when made available byorganic synthesis and when made available within the human or animalbody by way of cleavage of a pro-drug thereof. Accordingly, the presentspecification includes those compounds of the Formula (I), (IA), (IB),(IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), that are produced byorganic synthetic means and also such compounds that are produced in thehuman or animal body by way of metabolism of a precursor compound, thatis a compound of the Formula (I), (IA), (IB), (IC), (ID), (IE), (IF),(IH), (IJ), (IZ), or (IZA), may be a synthetically-produced compound ora metabolically-produced compound.

A suitable pharmaceutically acceptable pro-drug of a compound of theFormula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or(IZA), is one that is based on reasonable medical judgement as beingsuitable for administration to the human or animal body withoutundesirable pharmacological activities and without undue toxicity.

Various forms of pro-drug have been described, for example in thefollowing documents:—

-   a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder,    et al. (Academic Press, 1985);-   b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985);-   c) A Textbook of Drug Design and Development, edited by    Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and    Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991);-   d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);-   e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285    (1988);-   f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984);-   g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”,    A.C.S. Symposium Series, Volume 14; and-   h) E. Roche (editor), “Bioreversible Carriers in Drug Design”,    Pergamon Press, 1987.

The in-vivo effects of a compound of the Formula (I), (IA), (IB), (IC),(ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), may be exerted in part byone or more metabolites that are formed within the human or animal bodyafter administration of a compound of the Formula (I), (IA), (IB), (IC),(ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA). As stated hereinbefore,the in-vivo effects of a compound of the Formula (I), (IA), (IB), (IC),(ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), may also be exerted by wayof metabolism of a precursor compound (a pro-drug).

For the avoidance of doubt it is to be understood that where in thisspecification a group is qualified by ‘hereinbefore defined’ or ‘definedherein’ the said group encompasses the first occurring and broadestdefinition as well as each and all of the alternative definitions forthat group.

Another aspect of the present specification provides a process forpreparing a compound of the Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable saltthereof. A suitable process is illustrated by the followingrepresentative process variants in which, unless otherwise stated, A, D,E, G, Q and R¹ to R¹⁰ have any of the meanings defined hereinbefore.Necessary starting materials may be obtained by standard procedures oforganic chemistry. The preparation of such starting materials isdescribed in conjunction with the following representative processvariants and within the accompanying Examples. Alternatively, necessarystarting materials are obtainable by analogous procedures to thoseillustrated which are within the ordinary skill of an organic chemist.

Compounds of Formula (I) may be made by, for example:

a) Reaction of a compound of formula (II) with a compound of formula(III) under conditions known in the art as suitable for Pictet-Spenglerreactions (such as in the presence of acid (such as acetic acid) and ina suitable solvent (for example toluene) and a suitable temperature(such as 80-100° C.) with or without a protecting group (P) on thenitrogen that may be removed under conditions known to the art.

b) Where Q is O, NH or NMe, by etherification or amination of a suitablearyl halide of formula (IV), where L is for example a halogen (such asBr) or a trifluoromethanesulfonyl (triflate) group or a boronic acid orboronate ester, with an alcohol or amine of formula (V) using a suitablemetal catalyst (for example RockPhos 3rd Generation Precatalyst orBrettPhos 3rd Generation Precatalyst) in a suitable solvent (for exampletoluene, THF or DME) in the presence of a suitable base (for examplecesium carbonate or potassium carbonate) and a suitable temperature(such as 90-120° C.) with or without a protecting group (P) on thenitrogen that may be removed under conditions known to the art.

c) Where Q is O, by alkylation of a suitable phenol or hydroxylheteroaryl compound of formula (VI) with an alcohol of formula (V) viaMitsunobu reaction using appropriate reagents (such astriphenylphosphine and diisopropyl (E)-diazene-1,2-dicarboxylate) in asuitable solvent (such as DCM) with or without a protecting group (P) onthe nitrogen that may be removed under conditions known to the art.

d) Alkylation of a suitable compound of formula (VII), where LG is aleaving group known to the art, for example halide (such as Br),trifluoromethanesulfonate (triflate) or methanesulfonate (mesylate),with an amine of formula (VIII) in a suitable solvent (for exampleacetonitrile) in the presence of a suitable base (for example potassiumcarbonate) and a suitable temperature (such as 80-90° C.). with orwithout a protecting group (P) on the nitrogen that may be removed underconditions known to the art.

Compounds of formula (II) may be prepared by, for example:

a) Reaction of a compound of formula (IX) with an aldehyde of formula(X), in a suitable solvent (for example THF) in the presence of asuitable reducing agent (such as sodium triacetoxyborohydride) and at asuitable temperature (such as 20-30° C.);

b) (i) reaction of a compound of formula (IX) with an acid of formula(XI) under standard amide bond forming conditions (for example in thepresence of an amide coupling reagent (such as HATU) and a suitable base(such as triethylamine) in a suitable solvent (such as DMF)), followedby (ii) reduction of the resultant amide bond using a suitable reducingagent (such as borane) in a suitable solvent (such as THF) at a suitabletemperature (such as 60-70° C.);c) reaction of a compound of formula (IX) with a compound of formula(XII), wherein LG is a suitable leaving group (for example a halogenatom (such as bromo or chloro) or trifluoromethanesulfonate), in thepresence of a suitable base (such as diisopropylethylamine) in asuitable solvent (for example DCM or dioxane) and at a suitabletemperature (such as 20-85° C.).

Compounds of formula (III) may be prepared by reaction of a compound offormula (XIII) with an alcohol of formula (V) under conditions known inthe art as suitable for Mitsunobu reactions (such as in the presence ofan azodicarboxylate reagent (such as DEAD) and triphenylphosphine and ina suitable solvent (such as THF) and at a suitable temperature (such as20-30° C.).

Compounds of formula (IV) may be prepared by reaction of a compound offormula (II) with a compound of formula (XIV), where L is a suitablefunctional group such as halide (for example bromide or chloride),triflate, boronic acid or boronic ester, under conditions known in theart as suitable for Pictet-Spengler reactions, such as in the presenceof acid (such as acetic acid) and in a suitable solvent (for exampletoluene) and a suitable temperature (such as 80-100° C.).

Compounds of formula (VI) may be prepared by reaction of a compound offormula (II) with a compound of formula (XV), under conditions known inthe art as suitable for Pictet-Spengler reactions (such as in thepresence of acid (such as acetic acid) and in a suitable solvent (forexample toluene) and a suitable temperature (such as 80-100° C.). Incertain aspects X equals OH (optionally with a protecting group) or Xequals a boronic acid or boronic ester that may be converted to an OHusing a suitable oxidant (such as hydrogen peroxide) in the presence ofa suitable base (such as sodium hydroxide) in a suitable solvent (suchas THF).

Compounds of formula (VII) may be prepared by reaction of a compound offormula (VI) using standard functional group manipulations for example,a Mitsunobu reaction using appropriate reagents (such astriphenylphosphine and diisopropyl (E)-diazene-1,2-dicarboxylate) with2-haloethanol (such as 2-bromoethan-1-ol) in a suitable solvent (such asDCM).

Alternatively, compounds of formula (VII) may be prepared by reaction ofa compound of formula (IV) using standard functional group manipulationsfor example, an etherification, where L is for example a halogen (suchas Br) or a trifluoromethanesulfonyl (triflate) group or a boronic acidor boronate ester, with an appropriate diol (with optionalmono-protection) using a suitable metal catalyst (for example RockPhos3rd Generation Precatalyst) in a suitable solvent (for example tolueneor DME) in the presence of a suitable base (for example cesiumcarbonate). Subsequently, (with removal of protection if required) thealcohol may be converted into an appropriate leaving group (for examplehalide (such as Br), trifluoromethanesulfonate (triflate) ormethanesulfonate (mesylate)) under standard conditions.

It is to be understood that other permutations of the process steps inthe process variants described above are also possible.

When a pharmaceutically acceptable salt of a compound of Formula (I),(IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), isrequired it may be obtained by, for example, reaction of said compoundwith a suitable acid or suitable base. When a pharmaceuticallyacceptable pro-drug of a compound of Formula (I), (IA), (IB), (IC),(ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), is required, it may beobtained using a conventional procedure.

It will also be appreciated that, in some of the reactions mentionedhereinbefore, it may be necessary or desirable to protect any sensitivefunctionalities in the compounds. The instances where protection isnecessary or desirable, and suitable methods for protection, are knownto those skilled in the art. Conventional protecting groups may be usedin accordance with standard practice (for illustration see T. W. Green,Protective Groups in Organic Synthesis, John Wiley and Sons, 1991).Thus, if reactants include groups such as amino, carboxy or hydroxy, itmay be desirable to protect the group in some of the reactions mentionedherein.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ort-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an alkoxycarbonyl group such as a t-butoxycarbonyl groupmay be removed, for example, by treatment with a suitable acid ashydrochloric, sulfuric, formic, phosphoric or trifluoroacetic acid, andan arylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid, such as borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group, which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, an arylmethyl group, for example benzyl, or a trialkylor diarylalkyl silane, such as TBDMS or TBDPS. The deprotectionconditions for the above protecting groups will necessarily vary withthe choice of protecting group. Thus, for example, an acyl group such asan alkanoyl or an aroyl group may be removed, for example, by hydrolysiswith a suitable base such as an alkali metal hydroxide, for examplelithium or sodium hydroxide. Alternatively an arylmethyl group such as abenzyl group may be removed, for example, by hydrogenation over acatalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, such as trifluoroacetic acid, or forexample a benzyl group which may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art.

Certain of the intermediates defined herein are novel and these areprovided as further features of the specification.

Biological Assays

The following assays were used to measure the effects of the compoundsof the present specification.

ERα Binding Assay

The ability of compounds to bind to isolated Estrogen Receptor AlphaLigand binding domain (ER alpha—LBD (GST)) was assessed in competitionassays using a LanthaScreen Time-Resolved Fluorescence Resonance EnergyTransfer (TR-FRET) detection end-point. For the LanthaScreen TR-FRETendpoint, a suitable fluorophore (Fluormone ES2, ThermoFisher, Productcode P2645) and recombinant human Estrogen Receptor alpha ligand bindingdomain, residues 307-554 (expressed and purified in-house) were used tomeasure compound binding. The assay principle is that ER alpha-LBD (GST)is added to a fluorescent ligand to form a receptor/fluorophore complex.A terbium-labelled anti-GST antibody (Product code PV3551) is used toindirectly label the receptor by binding to its GST tag, and competitivebinding is detected by a test compound's ability to displace thefluorescent ligand, resulting in a loss of TR-FRET signal between theTb-anti-GST antibody and the tracer. The assay was performed as followswith all reagent additions carried out using the Beckman CoulterBioRAPTR FRD microfluidic workstation:

-   -   1. Acoustic dispense 120 nL of the test compound into a black        low volume 384 well assay plates.    -   2. Prepare 1× ER alpha-LBD/Tb-antiGST Ab in ES2 screening buffer        and incubate for 15 minutes.    -   3. Dispense 6 μL of the 1× AR-LBD/Tb-anti-GST Ab reagent into        each well of the assay plate followed by 6 μL of Fluorophore        reagent into each well of the assay plate    -   4. Cover the assay plate to protect the reagents from light and        evaporation, and incubate at room temperature for 4 hours.    -   5. Excite at 337 nm and measure the fluorescent emission signal        of each well at 490 nm and 520 nm using the BMG PheraSTAR.

Compounds were dosed directly from a compound source microplatecontaining serially diluted compound (4 wells containing 10 mM, 0.1 mM,1 μM and 10 nM final compound respectively) to an assay microplate usingthe Labcyte Echo 550. The Echo 550 is a liquid handler that usesacoustic technology to perform direct microplate-to-microplate transfersof DMSO compound solutions and the system can be programmed to transfermultiple small nL volumes of compound from the different source platewells to give the desired serial dilution of compound in the assay whichis then back-filled to normalise the DMSO concentration across thedilution range.

In total 120 nL of compound plus DMSO were added to each well andcompounds were tested in a 12-point concentration response format over afinal compound concentration range of 10, 2.917, 1.042, 0.2083, 0.1,0.0292, 0.0104, 0.002083, 0.001, 0.0002917, 0.0001042, and 0.00001 μMrespectively. TR-FRET dose response data obtained with each compound wasexported into a suitable software package (such as Origin or Genedata)to perform curve fitting analysis. Competitive ER alpha binding wasexpressed as an IC₅₀ value. This was determined by calculation of theconcentration of compound that was required to give a 50% reduction intracer compound binding to ER alpha-LBD.

MCF-7 ER Down-Regulation Assay

The ability of compounds to down-regulate Estrogen Receptor (ER) numberswas assessed in a cell based immuno-fluorescence assay using the MCF-7human ductal carcinoma breast cell line. MCF-7 cells were reviveddirectly from a cryovial (approx 5×10⁶ cells) in Assay Medium (phenolred free Dulbecco's Modified Eagle's medium (DMEM); Sigma D5921)containing 2 mM L-Glutamine and 5% (v/v) Charcoal/Dextran treated foetalcalf serum. Cells were syringed once using a sterile 18G×1.5 inch(1.2×40 mm) broad gauge needle and cell density was measured using aCoulter Counter (Beckman). Cells were further diluted in Assay Medium toa density of 3.75×10⁴ cells per mL and 40 μL per well added totransparent bottomed, black, tissue culture-treated 384 well plates(Costar, No. 3712) using a Thermo Scientific Matrix WellMate or ThermoMultidrop. Following cell seeding, plates were incubated overnight at37° C., 5% CO₂ (Liconic carousel incubator). Test data was generatedusing the LabCyte Echomodel 555 compound reformatter which is part of anautomated workcell (Integrated Echo 2 workcell). Compound stocksolutions (10 mM) of the test compounds were used to generate a 384 wellcompound dosing plate (Labcyte P-05525-CV1). 40 μL of each of the 10 mMcompound stock solutions was dispensed into the first quadrant well andthen 1:100 step-wise serial dilutions in DMSO were performed using aHydra II (MATRIX UK) liquid handling unit to give 40 μL of dilutedcompound into quadrant wells 2 (0.1 mM), 3 (1 μM) and 4 (0.01 μM),respectively. 40 μL of DMSO added to wells in row P on the source plateallowed for DMSO normalisation across the dose range. To dose thecontrol wells 40 μL of DMSO was added to row O1 and 40 μL of 100 μMfulvestrant in DMSO was added to row O3 on the compound source plate.

The Echo uses acoustic technology to perform directmicroplate-to-microplate transfers of DMSO compound solutions to assayplates. The system can be programmed to transfer volumes as low as 2.5nL in multiple increments between microplates and in so doing generatesa serial dilution of compound in the assay plate which is thenback-filled to normalise the DMSO concentration across the dilutionrange. Compounds were dispensed onto the cell plates with a compoundsource plate prepared as above producing a 12 point duplicate 3 μM to 3pM dose range with 3-fold dilutions and one final 10-fold dilution usingthe Integrated Echo 2 workcell. The maximum signal control wells weredosed with DMSO to give a final concentration of 0.3%, and the minimumsignal control wells were dosed with fulvestrant to give a finalconcentration of 100 nM accordingly. Plates were further incubated for18-22 hours at 37° C., 5% CO₂ and then fixed by the addition of 20 μL of11.1% (v/v) formaldehyde solution (in phosphate buffered saline (PBS))giving a final formaldehyde concentration of 3.7% (v/v). Cells werefixed at room temperature for 20 mins before being washed two times with250 μL PBS/Proclin (PBS with a Biocide preservative) using a BioTekplatewasher, 40 μL of PBS/Proclin was then added to all wells and theplates stored at 4° C. The fixing method described above was carried outon the Integrated Echo 2 workcell. Immunostaining was performed using anautomated AutoElisa workcell. The PBS/Proclin was aspirated from allwells and the cells permeabilised with 40 μL PBS containing 0.5% Tween™20 (v/v) for 1 hour at room temperature. The plates were washed threetimes in 250 μL of PBS/0.05% (v/v) Tween 20 with Proclin (PBST with aBiocide preservative) and then 20 μL of ERα (SP1) Rabbit monoclonalantibody (Thermofisher) 1:1000 in PBS/Tween™/3% (w/v) Bovine SerumAlbumin was added. The plates were incubated overnight at 4° C. (Liconiccarousel incubator) and then washed three times in 250 μL of PBS/0.05%(v/v) Tween™ 20 with Proclin (PBST). The plates were then incubated with20 μL/well of a goat anti-rabbit IgG AlexaFluor 594 or goat anti-rabbitAlexaFluor 488 antibody (Molecular Probes) with Hoechst at 1:5000 inPBS/Tween™/3% (w/v) Bovine Serum Albumin for 1 hour at room temperature.The plates were then washed three times in 250 μL of PBS/0.05% (v/v)Tween™ 20 with Proclin (PBST with a Biocide preservative). 20 μL of PBSwas added to each well and the plates covered with a black plate sealand stored at 4° C. before being read. Plates were read using aCellomics Arrayscan reading the 594 nm (24 hr time point) or 488 nm (5hr timepoint) fluorescence to measure the ERα receptor level in eachwell. The mean total intensity was normalized for cell number giving thetotal intensity per cell. The data was exported into a suitable softwarepackage (such as Origin) to perform curve fitting analysis.Down-regulation of the ERα receptor was expressed as an IC₅₀ value andwas determined by calculation of the concentration of compound that wasrequired to give a 50% reduction of the average maximum Total Intensitysignal.

The data shown in Table A were generated (the data below may be a resultfrom a single experiment or an average of two or more experiments):

TABLE A ER binding IC₅₀ ER down regulation Example value (nM) IC₅₀ value(nM) 1 12 3.7 2 34 49 3 180 98 4 2.6 0.28 5 45 25 6 2.1 0.19 7 1.5 0.128 1.4 0.20 9 1.2 0.088 10 2.9 0.23 11 1.2 0.14 12 0.62 0.059 13 1.6 0.2214 0.69 0.092 15 0.55 0.079 16 1.7 3.7 17 3.8 1.6 18 10 6.2 19 360 11020 1.0 0.29 21 2.6 1.6 22 1.4 0.12 23 2.7 0.5 24 2.0 0.85 25 0.88 0.2526 0.85 0.16 27 2.7 1.6 28 2.8 0.8 29 2.0 0.44 30 2.1 0.32 31 5.4 7.2 322.7 0.38 33 1.6 0.081 34 190  — (41%) 35 1.9 1.1 36 2.6 0.35 37 12 35 38NT 0.19 39 1.4 0.26 40 7.9 0.53 41 12 6.0 42 3.7 1.9 43 82 220 44 1.00.14 45 0.78 0.034 46 1.0 0.22 47 2.5   11 (81%) 48 4.4 13 49 1.2 0.1550 1.0 0.81 (81%) 51 1.2 0.12 52 0.58 0.34 53 150  — (40%) 54 5.9 1.0 554.0 0.53 56 39 14 57 2.6 0.34 58 7.9 1.9 59 2.3 3.1 60 0.84 0.12 61 0.790.19 62 0.71 0.076 63 1.1 0.32 64 0.96 0.071 65 0.64 0.058 66 0.71 0.3467 0.70 0.099 68 0.69 0.095 69 1.4 1.5 70 1300 180 71 3.4  2.0 (90%) 721.4 0.49 73 9.4 18 74 31 59 75 52 58 76 1.0 0.21 77 7.3 6.2 78 1.3 0.1279 1.4 0.16 80 2.0 1.2 81 >110 0.17 82 0.80 0.042 83 1.7 0.28 (90%) 840.94 0.16 (83%) 85 1.3 0.089 86 0.86 0.17 87 0.54 0.065 88 2.2 0.28 890.91 0.14 90 0.65 0.3 91 9.4 15 92 1.6 0.4 93 1.4 0.39 94 3.6 9.2 95 5.63.3 96 1.4 0.2 97 2.2 0.66 98 1.9 1.2 99 3.4 3.8 100 5.2 11 101 9.2 27102 2.0 2.9 103 0.56 0.084 104 0.72 0.17 105 42 39 106 0.92 0.095 1071.3 0.21 108 1.0 0.3 109 1.2 0.41 110 0.43 0.045 111 0.60 0.07 112 2.00.95 113 17 >300 114 0.74 0.2 115 1.0 0.31 116 15 1.1 117 9.2 0.92 1181.2 5.5 119 6.9 1.0 120 11 2.5 121 2.8 0.53 122 4.9 0.39 123 11 0.96 1243.9 0.68 125 1.3 0.62 126 1.2 0.43 127 1.8 0.49 128 3.4 1.1 129 8.9 2.6130 1.8 1.3 131 13 2.4 132 2.0 0.98 133 1.5 1.5 134 5.8  1.6 (85%) 135160 16 136 2.0 >300 137 1.7 0.52 138 1.6 1.6 139 1.5 0.9 140 1.4 1.0 1412.8 0.98 142 1.5 0.95 143 2.1 0.39 144 5.6  7.9 (88%) 145 1.1 0.35 1461.1 0.4 147 51 NT 148 1.1 0.42 (68%) 149 1.5 0.85 (86%) 150 5.2 0.53 1518.2 1.1 152 1.5 0.38 153 2.2 0.44 154 1.2 0.89 (79%) 155 1.0 0.21 1561.2 1.4 157 1.8 1.0 158 1.5 1.0 159 0.9 0.18 160 1.9 0.36 161 1.7 1.1162 1.4 0.48 163 3.3 1.2 ¹Compounds tested in the ER down regulationassay show downregulation values (>90%) in the assay unless otherwisestated, in which case the % downregulation is shown in brackets. (NT =not tested).

Western Blotting Assay

The ability of compounds to down-regulate estrogen receptor (ER) wasassessed by western blotting using human breast cancer cell lines (MCF-7and CAMA-1). Cells were plated into 12-well tissue culture-treatedplates at 0.5×10⁶/well in phenol red-free RPMI containing 2 mML-glutamine and 5% (v/v) charcoal treated foetal calf serum (F6765,Sigma). Cells were incubated with compounds (100 nM) or vehicle control(0.1% DMSO) for 48 h at 37° C., 5% CO₂ before washing once with PBS andlysing with 80 μl lysis buffer (25 mM Tris/HCl, 3 mM EDTA, 3 mM EGTA, 50mM NaF, 2 mM sodium orthovanadate, 0.27 M sucrose, 10 mMβ-glycerophosphate, 5 mM sodium pyrophosphate, 0.5% TritonX-100, pH 6.8)on ice.

Cells were scraped, sonicated and centrifuged prior to performing aprotein assay (DC Bio-Rad Protein kit, 500-0116) and making samples to aprotein concentration of 1-2 mg/mL in lysis buffer containing 1×LDSSample Buffer (NP0007, Invitrogen) and 1× NuPAGE sample reducing agent(NP0009, Invitrogen). Samples were boiled for 10 min at 95° C. and thenfrozen at −20° C. until ready for use.

10-20 μg protein was loaded onto 26-well Criterion gels (BioRad345-0034). Gels were run at 125 V for 1 hr 25 min in running buffer (24mM Tris Base Sigma, 192 mM Glycine, 3.5 mM SDS, made up in distilledwater). Gels were then transferred at 30V for 2 hr in transfer buffer(25 mM Tris, 192 mM Glycine, 20% (v/v) methanol, pH 8.3, made up indistilled water) onto nitrocellulose membrane. The blot was stained withPonceau S (P7170, Sigma) and cut according to appropriate molecularweight markers.

Membranes were blocked for 1 hour at room temp in 5% Marvel (w/v) inphosphate-buffered saline containing 0.05% Tween™ 20 (PBS/Tween). Blotswere then incubated with anti-ERα (SP1) rabbit monoclonal antibody(Thermofisher) diluted 1:1000 at 4° C. overnight (with gentle shaking)followed by several washes with PBS/Tween. Secondary anti-rabbit HRPantibody (7074, CST) diluted 1:2000 dilution was incubated for 2 h atroom temperature (with gentle shaking) followed by several washes withPBS/Tween. All antibodies were made up in 5% Marvel (w/v) in PBS/Tween.

The immunoblots were developed using Pierce WestDura chemiluminescentreagents (Thermo Scientific 34076) and developed/quantified on the G-boxusing Syngene software. Down-regulation of the ERα receptor wasnormalised to the vehicle control (0% down-regulation) and the 100 nMfulvestrant control (100% down-regulation) run within the same gel.

Table B shows the data generated for selected Examples (the data belowmay be a result from a single experiment or an average of two or moreexperiments):

TABLE B CAMA1 Western MCF7 Western Example % ER deg vs Fv % ER deg vs Fv1 66 79 4 75 56 6 81 97 7 90 100 8 93 98 9 101 97 10 101 94 11 92 94 1289 92 13 92 83 14 95 95 15 91 94 16 83 89 19 103 101 20 91 88 21 95 9922 96 96 23 95 95 35 92 94 40 70 86 44 94 95 45 93 89 46 89 83 51 93 9255 94 89 57 88 93 58 83 76 60 97 92 61 83 94 62 96 95 63 85 94 64 98 9665 97 94 76 85 92 88 93 90 90 93 76 92 91 93 96 100 94 97 84 89 107 9895 110 83 91 111 92 84 117 92 96 121 107 85 123 90 91 124 82 93 126 8993 127 100 96 133 86 88 137 95 90 140 86 84 141 NT 79 142 80 85 143 7187 145 87 94 152 90 93

Human Hepatocyte Assay

The metabolic stability of compounds in human hepatocytes was assessedusing the following protocol:

-   -   1. Prepare 10 mM stock solutions of compound and control        compounds in appropriate solvent (DMSO). Place incubation medium        (L-15Medium) in a 37° C. water bath, and allow warming for at        least 15 minutes prior to use.    -   2. Add 80 μL of acetonitrile to each well of the 96-well deep        well plate (quenching plate).    -   3. In a new 96-well plate, dilute the 10 mM test compounds and        the control compounds to 100 μM by combining 198 μL of        acetonitrile and 2 μL of 10 mM stock.    -   4. Remove a vial of cryopreserved (less than −150° C.) human        hepatocytes (LiverPool Donor Human hepatocytes obtained from        Celsis IVT. Chicago, Ill. (Product No. S01205)) from storage,        ensuring that vials remain at cryogenic temperatures until        thawing process ensues. As quickly as possible, thaw the cells        by placing the vial in a 37° C. water bath and gently shaking        the vials. Vials should remain in water bath until all ice        crystals have dissolved and are no longer visible. After thawing        is complete, spray vial with 70% ethanol, transfer the vial to a        bio-safety cabinet.    -   5. Open the vial and pour the contents into the 50 mL conical        tube containing thawing medium. Place the 50 mL conical tube        into a centrifuge and spin at 100 g for 10 minutes. Upon        completion of spin, aspirate thawing medium and resuspend        hepatocytes in enough incubation medium to yield˜1.5×10⁶        cells/mL.    -   6. Using Cellometer Vision, count cells and determine the viable        cell density. Cells with poor viability (<80% viability) are not        acceptable for use. Dilute cells with incubation medium to a        working cell density of 1.0×10⁶ viable cells/mL.    -   7. Transfer 247.5 μL of hepatocytes into each well of a 96-well        cell culture plate. Place the plate on Eppendorf Thermomixer        Comfort plate shaker to allow the hepatocytes to warm for 10        minutes.    -   8. Add 2.5 μL of 100 μM test compound or control compounds into        an incubation well containing cells, mix to achieve a homogenous        suspension at 0.5 min, which when achieved, will define the 0.5        min time point. At the 0.5 min time, transfer 20 μL of incubated        mixture to wells in a “Quenching plate” followed by vortexing.    -   9. Incubate the plate at 37° C. at 900 rpm on an Eppendorf        Thermomixer Comfort plate shaker. At 5, 15, 30, 45, 60, 80, 100        and 120 min, mix the incubation system and transfer samples of        20 μL incubated mixture at each time point to wells in a        separate “Quenching plate” followed by vortexing.    -   10. Centrifuge the quenching plates for 20 minutes at 4,000 rpm.        4 different compounds are pooled into one cassette and used for        LC/MS/MS analysis.

All calculations were carried out using Microsoft Excel. Peak areas weredetermined from extracted ion chromatograms. In vitro intrinsicclearance (in vitro Cl_(int), in L/min/10⁶ cells) of parent compound wasdetermined by regression analysis of the Ln percent parent disappearancevs. time curve. The in vitro intrinsic clearance (in vitro Cl_(int), inL/min/10⁶ cells) was determined from the slope value using the followingequation and is shown in Table C:

in vitro Cl_(int) =kV/N

V=incubation volume (0.25 mL);

N=number of hepatocytes per well (0.25×10⁶ cells).

TABLE C Cl_(int) (μL/min/10⁶ Example cells) 9 4 14 6 55 <1 57 2 121 <1123 <1 126 <1 127 <1 143 4 145 5 151 <1 152 2 157 2 160 1

Physical Properties LogD

The lipophilicity of a drug is an important physical property which mayinfluence many biological and metabolic properties of a compound, forexample the absorption, distribution, metabolism, excretion and toxicityprofiles of a compound. The distribution coefficient between 1-octanoland aqueous buffer, LogDO/W, at pH 7.4, is the most commonly usedmeasurement of the lipophilicity of a compound. The current method formeasurement of LogDO/W is based on the traditional shake flasktechnique, but with the modification of measuring compounds in mixturesoften at a time using UPLC with quantitative mass spectrometry (MS) as amethod to measure the relative octanol and aqueous concentrations. Themaximum capacity is 379 project compounds (48 pools with 10 compoundsincl. three QC compounds) per experiment. 2 quality control (QC)samples, Cyclobenzaprine with moderate LogD and Nicardipine high LogD isused in all pools to ensure good quality. An additional QC sampleCaffeine, with low LogD, are used and randomly placed in all runs. Themethod has been thoroughly validated against the previous shake flaskmethodologies.

Solubility

In order for an oral compound to reach the site of action, and in orderfor oral absorption from the gut to occur, that compound must be insolution, and therefore compounds which possess high intrinsicsolubility may be more suitable for pharmaceutical use. Thethermodynamic solubility of a research compound is measured understandard conditions. It is a shake-flask approach that uses 10 mM DMSOsolutions which are supplied from the Compound Managements liquid storeand is a high throughput method. The dried compounds are equilibrated inan aqueous phosphate buffer (pH 7.4) for 24 hours at 25° C., the portionwith the dissolved compound is then separated from the remains. Thesolutions are analyzed and quantified using UPLC/MS/MS, QC-samples areincorporated in each assay-run to ensure the quality of the assay.

Human Plasma Protein Binding

Human plasma protein binding is a key factor in controlling the amountof free (unbound) drug available for binding to target and hence playsan important role in the observed efficacy of drugs in vivo. Therefore,compounds which possess high free fraction (low levels of plasma proteinbinding) may exhibit enhanced efficacy relative to a compound withsimilar potency and exposure levels. The automated equilibrium dialysisassay in human plasma uses the RED (Rapid Equilibrium Dialysis) Deviceand sample handling. The assay generally runs over two to three daysincluding delivery of results. After dialysis for 18 hours, plasma andbuffer samples are prepared for analysis by liquid chromatography andmass spectrometry. Samples are generally tested in singlicates andquantified by LC/MSMS by using a 7-point calibration curve in plasma.The compounds are pooled together in plasma pools up to 10 compounds.Three reference compounds are used in each run, Propranolol, Metoprololand Warfarin. Warfarin is used as a control in each pool and Propranololand Metoprolol are placed randomly in each run. An in-house Excel macrois used for preparation of files for the robot and the mass spectrometerand is also used for the calculations of fraction unbound (fu %) inplasma.

Table D shows the data for log D, solubility and plasma protein bindinggenerated for selected Examples (the data below may be a result from asingle experiment or an average of two or more experiments):

TABLE D Human plasma LogD Solubility protein binding Example pH 7.4 (μM)(% free) 1 3.0 303 6.5 2 3.1 895 3.8 3 3.0 712 2.6 4 2.5 543 10 5 3.0357 2.8 6 3.2 154 2.2 7 3.7 35 1.5 8 2.6 617 5.6 9 3.6 100 1.6 10 3.6 672.0 11 3.4 102 0.85 13 2.6 493 3.5 14 2.4 606 4.0 15 2.9 571 3.2 16 4.174 1.2 17 4.0 68 0.36 18 4.5 27 0.55 19 4.6 5 0.49 20 4.6 11 0.24 21 4.63 0.10 22 4.2 0.7 0.61 23 3.4 73 3.7 24 3.7 88 0.84 25 4.3 19 0.080 264.6 8 0.22 27 4.2 6 0.42 28 3.8 40 1.2 29 >3.2 58 <3.2 30 4.1 39 0.72 314.1 40 0.41 32 4.1 55 0.52 33 4.5 8 0.090 34 3.7 151 2.2 35 3.1 222 5.436 3.5 183 2 37 3.6 434 2.3 38 NT NT 0.91 39 3.6 259 NT 40 3.0 366 0.8941 2.9 242 1.8 42 2.9 349 NT 43 2.2 358 2.8 44 3.3 278 2.3 45 3.3 2271.2 46 2.8 462 2.4 47 2.7 488 6.1 48 2.8 307 NT 49 2.8 335 NT 50 2.8 4617.1 51 3.2 122 2.3 52 3.0 426 3.3 53 0.1 >1000 80 54 0.9 >1000 18 55 0.9875 26 56 2.7 445 4.6 57 1.3 >1000 17 58 0.4 >1000 38 59 0.9 >1000 28 603.0 351 1.9 61 3.0 446 2.0 62 3.3 302 1.2 63 3.1 273 0.97 64 2.7 944 5.465 3.0 462 1.9 66 3.0 441 1.3 67 4.0 80.6 1.6 68 3.2 56.6 1.2 69 3.6 1502.2 70 2.2 231 23 71 3.8 <1.6 0.44 72 5.2 <0.2 <0.1 73 4.4 7 0.24 74 4.10.9 0.61 75 4.5 0.9 0.08 76 3.1 147 4.6 77 2.4 410 5.5 78 4.0 26 0.21 794.8 3.9 <0.4 80 4.5 13 0.12 81 2.6 736 2.9 82 2.9 475 1.9 83 2.9 595 2.584 2.4 640 6 85 3.1 224 1.0 86 2.9 385 2.6 87 3.1 71 1.6 88 3.4 118 0.5889 2.7 670 <3.4 90 2.8 365 1.1 91 2.9 280 0.93 92 2.7 468 NT 93 4.3 0.50.34 94 2.4 698 7 95 2.5 869 4.6 96 2.4 960 7.1 97 1.8 >1000 6.8 98 2.3594 NT 99 2.1 285 NT 100 2.5 >1000 NT 101 3.3 329 8.4 102 3.8 251 1.4103 2.9 660 2 104 3.0 431 2.8 105 3.4 136 1 106 3.9 264 0.34 107 3.6 1201 108 3.2 375 2.3 109 >3.6 176 1.9 110 3.1 939 NT 111 3.1 469 1.4 1123.2 92 1.5 113 4.1 <1.6 NT 114 3.3 276 1.7 115 2.1 983 11 116 0.3 >100058 117 0.8 948 46 118 1.8 111 8.4 119 1.3 >1000 31 120 NT NT NT 1211.4 >1000 30 122 1.1 >1000 18 123 1.1 954 36 124 1.3 958 14 125 0.9 9787.4 126 1.2 966 15 127 1.8 952 24 128 1.0 973 15 129 1.5 953 23 130 1.5854 7.8 131 1.2 >1000 32 132 0.6 914 34 133 1.2 772 16 134 0.6 >1000 36135 0.5 >1000 32 136 1.1 328 2.1 137 1.4 >1000 11 138 1.6 995 8.3 1391.0 916 13 140 1.7 775 5.7 141 1.5 638 5.2 142 1.4 796 6.2 143 1.5 >100028 144 NT NT NT 145 1.8 >1000 15 146 1.9 887 14 147 NT NT 19 148 1.5 78810 149 2.2 523 5.3 150 1.3 924 32 151 1.0 >1000 45 152 1.9 860 20 1531.9 >1000 22 154 3.5 49 2.7 155 2.3 978 9.2 156 1.7 882 18 157 1.2 94329 158 1.8 >1000 21 159 1.7 >1000 13 160 1.7 951 32 161 1.3 >1000 6.3162 1.8 >1000 27 163 0.7 >1000 49 (NT = Not tested)hERG Binding Assay

hERG (human ether a go go-related gene) potassium channels are essentialfor normal electrical activity in the heart. Arrhythmia can be inducedby a blockage of hERG channels by a diverse group of drugs. This sideeffect is a common reason for drug failure in preclinical safety trials[Sanguinetti et al., Nature., 2006, 440, 463-469.] and thereforeminimisation of hERG channel blocking activity may be a desirableproperty for drug candidates.

The purpose of the hERG binding assay is to evaluate the effects of testcompounds on the voltage-dependent potassium channel encoded by thehuman ether go go-related gene (hERG) using a constitutively expressingCHO cell line on the Nanion Syncropatch 384PE automated patch clampsystem.

The assay was conducted as follows with all reagents used at roomtemperature unless otherwise stated.

Reagent preparations include:

1. Internal “IC700” solution used to perfuse the underside of chip (inmM), KF 130, KCl 20, MgCl2 1, EGTA 10 and HEPES 10, (all Sigma-Aldrich;pH 7.2-7.3 using 10 M KOH, 320 mOsm) and supplemented with 25 μM escin.2. External and cell buffer (in mM), NaCl 137, KCl 4, HEPES 10,D-glucose 10, CaCl2 2, MgCl2 1 (pH7.4, NaOH)3. NMDG “reference” buffer used to establish a stable baseline prior tothe addition of test compounds, NaCl 80, KCl 4, CaCl2 2, MgCl2 1, NMDGCl 60, D-Glucose monohydrate 5, HEPES 10 (pH7.4 NaOH 298 mOsm)4. Seal enhancer used to improve seal quality of cells, NaCl 80, KCl 3,CaCl2 10, HEPES 10, MgCl2 1 (pH7.4 NaOH)

Cell Preparations:

1. If using cell culture; cells to be incubated at 30° C. forapproximately 4-6 days prior to being used. Day of assay lift cellsusing accutase and re-suspend in 20 ml cell buffer to a density of 0.8to 1e6 cells/ml.2. If using assay ready cryovials; rapidly thaw two cryovials at 37° C.and slowly pipette into 23 ml external solution3. All cell preps to be incubated for 15 min on the shaking cell hotelset to 10° C. prior to starting assay

Compound Preparations:

All compounds were acoustically dispensed in quadruplicate using aLabcyte Echo. A 10 mM stock solution is used to generate 6 compoundsource plates each at a different concentration to allow cumulativedosing onto cells (0.03167 mM, followed by 0.1 mM, then 0.3167 mM, 1 mM,3.167 mM, 10 mM,). 90 μl of reference buffer is added to each well ofthe source plates containing 600 nl of compound for a final compoundconcentration of 0.1 μM, 0.39 μM, 1.2 μM, 3.9 μM, 12.5 μM and 39.6 μMrespectively.

hERG assay (all dispense steps are performed using the liquid handlingset up on the Nanion syncropatch)

1. Fill 384 well medium resistance 4 hole chips with 40 μl externalbuffer and perfuse internal buffer to the underside of plate.2. Dispense 20 μl of cells into each well of the chip followed by 20 μlof seal enhancer.3. Remove 40 μl of reagent from each well to the wash station, leaving aresidual volume of 40 μl4. Dispense 40 μl of reference buffer with a removal step of 40 μl after3 min, repeat this step.5. Dispense 40 μl of compound plate 1 (0.03167 mM), ‘real time’recordings for 3 min exposure prior to removal of 40 μl. This step isrepeated for 5 further subsequent compound plates in increasingconcentrations to generate a cumulative concentration-effect curve ineach well of the Syncropatch chip.

hERG-mediated currents were elicited using a voltage step protocolconsisting of acontinuous holding voltage of −80 mV, with a 500 ms stepto 60 mV followed by a 500 ms step to −40 mV every 15 seconds. hERGcurrent magnitude was measured automatically from the leak-subtractedtraces by the Nanion software by taking the peak of the hERG “tail”current at −40 mV every 15 seconds and taking the last three of theseresponses for each concentration to generate the concentration-effectcurve.

Calculation of results is performed using APC package within Genedata.For the routine normalization of well data with Neutral and Inhibitorcontrol well groups as reference, GeneData Assay Analyzer uses thefollowing equation to normalize the signal values to the desired signalrange:

${N(x)} = {{CR} + {\frac{{x -} < {cr} >}{< {sr} > {- {< {cr} >}}}\left( {{SR} - {CR}} \right)}}$

x is the measured raw signal value of a well<cr> is the median of the measured signal values for the CentralReference (Neutral) wells on a plate<sr> is the median of the measured signal values for the Scale Reference(Inhibitor) wells on a plateCR is the desired median normalized value for the Central Reference(Neutral)SR is the desired median normalized value for the Scale Reference(Inhibitor)

Table E shows the hERG binding data for selected Examples (the databelow may be a result from a single experiment or an average of two ormore experiments):

TABLE E hERG IC₅₀ Example (μM) 1 4.4 6 5.4 7 3.8 8 4.6 9 9.6 10 3.6 115.4 12 8.2 13 2.6 14 5.1 15 4.6 17 4.1 18 4.5 20 3.8 22 4.2 23 5.4 24 725 5.2 26 4.1 27 4.8 28 3.6 29 5.1 30 2.3 31 11 32 5.8 33 5.3 34 3.4 355.6 36 8.7 37 3.5 38 5 39 3.9 40 4.1 41 4.9 42 7.1 43 3.1 44 2.9 45 1.546 2.7 47 3.2 48 2.7 49 5.6 50 5.3 51 4.1 52 5.5 53 >40 54 >40 55 >4057 >40 58 >40 59 >40 60 4.4 61 2.7 62 5 63 4.7 64 6.1 65 9.4 66 5.4 675.7 68 2 69 2.7 70 6.3 71 5.8 73 6.7 74 12 75 7.7 76 4.2 77 5.4 79 10 8010 81 3.9 82 4.3 83 4 84 2.8 85 4.2 86 3.9 87 2.4 88 4.8 89 6.1 90 5 912.6 92 23 93 6.6 94 9.9 95 7.2 96 10 97 18 98 >32 99 20 100 19 101 7.1102 7.2 103 4.3 104 4.3 105 3.5 106 7.3 107 8.1 108 6 110 2.8 111 5.1112 19 114 5.9 115 11 117 >40 119 >40 121 >40 123 >40 125 >40 126 >40128 >40 132 >40 133 >40 137 >40 138 >40 140 >40 143 >40 145 >40 149 >40151 >40 152 >40 154 4.3 156 >40 157 >40 158 >40 159 >40 161 >40 162 >40

Permeability

In order to maximize oral absorption, a drug must have sufficienttransmembrane flux as well as avoid efflux by P-glycoprotein. The mostwidely used system for predicting oral absorption by determination ofthe permeation rate of compounds through monolayers of a human colonadenocarcinoma cell line Caco-2.

Human Caco-2 Bidirectional Permeability A to B and B to A

An automated assay was used to determine the bidirectional permeability(efflux and uptake) of compounds in Caco-2 cells carried out over 2hours at pH 7.4. Samples were analyzed through LC/MS/MS to estimate theapparent permeability coefficients (Papp) of compounds across Caco-2cell monolayers and results are quoted in units of ×10⁻⁶ cm/s.

The efflux ratio (ER) can be determined using the following equation:

ER=P _(app)(B−A)/P _(app)(A−B)

Where P_(app (B-A)) indicates the apparent permeability coefficient inbasolateral to apical direction, and P_(app (A-B)) indicates theapparent permeability coefficient in apical to basolateral direction.

Human Caco-2 Passive Permeability A to B Papp

An automated assay was used to determine the passive permeability ofcompounds in Caco-2 cell monolayers carried out over 2 hours with anapical pH of 6.5 and basolateral pH of 7.4. The Caco-2 AB inhibitionassay is carried out with chemical inhibition of the three major effluxtransporters ABCB1 (P-gp), ABCG2 (BCRP) and ABCC2 (MRP2) in Caco-2cells. Incubation of both apical and basolateral is carried out with acocktail of inhibitors (50 μM quinidine, 20 μM sulfasalazine and 100 μMbenzbromarone). Samples were analyzed through LC/MS/MS to estimate theapparent permeability coefficients (Papp) of compounds across Caco-2cell monolayers and results are quoted in units of ×10⁻⁶ cm/s.

Table F shows the data for permeability generated for selected Examples(the data below may be a result from a single experiment or an averageof two or more experiments):

TABLE F Bidirectional Bidirectional Passive Caco-2 Papp Caco-2 Caco-2Papp Example (×10⁻⁶ cm/s) efflux ratio (×10⁻⁶ cm/s) 9 1.0 1.0 NT 10 1.41.6 NT 11 3.6 1.4 NT 14 4.4 1.3 13 52 8.8 1.0 NT 55 0.55 23 <0.7 57 0.15105 <1.2 59 0.035 480 <0.3 64 2.6 6.1 NT 76 6.4 0.55 NT 117 0.27 34 <0.3119 0.85 25 3.5 121 0.20 58 NT 122 0.58 40 <1.0 123 1.1 16 <1.0 124 1.123 1.9 125 0.13 130 <0.6 126 0.46 52 1.2 127 0.43 48 2.0 133 0.29 51 2.5137 0.35 64 4.6 138 0.16 94 1.8 139 0.26 54 <0.9 140 0.51 36 4.0 1410.54 36 3.4 142 0.34 40 3.2 143 3.2 11 3.3 144 0.50 35 4.0 145 5.6 3.417 151 2.2 9.5 4.3 152 11 2.2 16 155 7.3 2.6 23 156 4.6 4.2 9.2 157 3.65.6 12 160 4.4 6.4 4.2 (NT = Not Tested)

According to a further aspect of the specification there is provided apharmaceutical composition, which comprises a compound of the Formula(I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), ora pharmaceutically acceptable salt thereof, as defined hereinbefore inassociation with a pharmaceutically acceptable excipient.

Suitable pharmaceutically acceptable excipients for a tablet formulationinclude, for example, inert diluents, granulating and disintegratingagents, binding agents, lubricating agents, preservative agents andantioxidants. A further suitable pharmaceutically acceptable excipientmay be a chelating agent. Tablet formulations may be uncoated or coatedeither to modify their disintegration and the subsequent absorption ofthe active ingredient within the gastrointestinal tract, or to improvetheir stability and/or appearance, in either case, using conventionalcoating agents and procedures well known in the art.

Compositions for oral use may alternatively be in the form of hardgelatin capsules in which the active ingredient is mixed with an inertsolid diluent, or as soft gelatin capsules in which the activeingredient is mixed with water or an oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, dispersing orwetting agents. The aqueous suspensions may also contain one or morepreservatives, anti-oxidants, colouring agents, flavouring agents,and/or sweetening agents.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil or in a mineral oil. The oily suspensions may alsocontain a thickening agent. Sweetening agents such as those set outabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Additional excipients such as sweetening,flavouring and colouring agents, may also be present.

The pharmaceutical compositions of the specification may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oil ora mineral oil or a mixture of any of these. The emulsions may alsocontain sweetening, flavouring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents, and mayalso contain a demulcent, preservative, flavouring and/or colouringagent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solventsystem.

Compositions for administration by inhalation may be in the form of aconventional pressurised aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient. Dry powder inhalers may also be suitable.

For further information on formulation the reader is referred to Chapter25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch;Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, oral administration to humans willgenerally require, for example, from 1 mg to 2 g of active agent (moresuitably from 100 mg to 2 g, for example from 250 mg to 1.8 g, such asfrom 500 mg to 1.8 g, particularly from 500 mg to 1.5 g, convenientlyfrom 500 mg to 1 g) to be administered compounded with an appropriateand convenient amount of excipients which may vary from about 3 to about98 percent by weight of the total composition. It will be understoodthat, if a large dosage is required, multiple dosage forms may berequired, for example two or more tablets or capsules, with the dose ofactive ingredient divided conveniently between them. Typically, unitdosage forms will contain about 10 mg to 0.5 g of a compound of thisspecification, although a unit dosage form may contain up to 1 g.Conveniently, a single solid dosage form may contain between 1 and 300mg of active ingredient.

The size of the dose for therapeutic or prophylactic purposes ofcompounds of the present specification will naturally vary according tothe nature and severity of the disease state, the age and sex of theanimal or patient and the route of administration, according to wellknown principles of medicine.

In using compounds of the present specification for therapeutic orprophylactic purposes it will generally be administered so that a dailydose in the range, for example, 1 mg/kg to 100 mg/kg body weight isreceived, given if required in divided doses. In general, lower doseswill be administered when a parenteral route is employed. Thus, forexample, for intravenous administration, a dose in the range, forexample, 1 mg/kg to 25 mg/kg body weight will generally be used.Similarly, for administration by inhalation, a dose in the range, forexample, 1 mg/kg to 25 mg/kg body weight will be used. Oraladministration is however preferred, particularly in tablet form.

In one aspect of the specification, compounds of the presentspecification or pharmaceutically acceptable salts thereof, areadministered as tablets comprising 10 mg to 100 mg of the compound ofthe specification (or a pharmaceutically acceptable salt thereof),wherein one or more tablets are administered as required to achieve thedesired dose.

As stated above, it is known that signalling through ERα causestumourigenesis by one or more of the effects of mediating proliferationof cancer and other cells, mediating angiogenic events and mediating themotility, migration and invasiveness of cancer cells. We have found thatthe compounds of the present specification possess potent anti-tumouractivity which it is believed is obtained by way of antagonism anddown-regulation of ERα that is involved in the signal transduction stepswhich lead to the proliferation and survival of tumour cells and theinvasiveness and migratory ability of metastasising tumour cells.

Accordingly, the compounds of the present specification may be of valueas anti-tumour agents, in particular as selective inhibitors of theproliferation, survival, motility, dissemination and invasiveness ofmammalian cancer cells leading to inhibition of tumour growth andsurvival and to inhibition of metastatic tumour growth. Particularly,the compounds of the present specification may be of value asanti-proliferative and anti-invasive agents in the containment and/ortreatment of solid tumour disease. Particularly, the compounds of thepresent specification may be useful in the prevention or treatment ofthose tumours which are sensitive to inhibition of ERα and that areinvolved in the signal transduction steps which lead to theproliferation and survival of tumour cells and the migratory ability andinvasiveness of metastasising tumour cells. Further, the compounds ofthe present specification may be useful in the prevention or treatmentof those tumours which are mediated alone or in part by antagonism anddown-regulation of ERα, i.e. the compounds may be used to produce an ERαinhibitory effect in a warm-blooded animal in need of such treatment.

According to a further aspect of the specification there is provided acompound of the Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH),(IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, asdefined hereinbefore for use as a medicament in a warm-blooded animalsuch as man.

According to a further aspect of the specification, there is provided acompound of the Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH),(IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, asdefined hereinbefore for use in the production of an anti-proliferativeeffect in a warm-blooded animal such as man.

According to a further aspect of the specification there is provided acompound of the Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH),(IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, asdefined hereinbefore for use in a warm-blooded animal such as man as ananti-invasive agent in the containment and/or treatment of solid tumourdisease.

According to a further aspect of the specification, there is providedthe use of a compound of the Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable saltthereof, as defined hereinbefore, for the production of ananti-proliferative effect in a warm-blooded animal such as man.

According to a further aspect of the specification there is provided theuse of a compound of the Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable saltthereof, as defined hereinbefore, in the manufacture of a medicament foruse in the production of an anti-proliferative effect in a warm-bloodedanimal such as man.

According to a further aspect of the specification there is provided theuse of a compound of the Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable saltthereof, as defined hereinbefore, in the manufacture of a medicament foruse in a warm-blooded animal such as man as an anti-invasive agent inthe containment and/or treatment of solid tumour disease.

According to a further aspect of the specification there is provided amethod for producing an anti-proliferative effect in a warm-bloodedanimal, such as man, in need of such treatment which comprisesadministering to said animal an effective amount of a compound of theFormula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or(IZA), or a pharmaceutically acceptable salt thereof, as definedhereinbefore.

According to a further aspect of the specification there is provided amethod for producing an anti-invasive effect by the containment and/ortreatment of solid tumour disease in a warm-blooded animal, such as man,in need of such treatment which comprises administering to said animalan effective amount of a compound of the Formula (I), (IA), (IB), (IC),(ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceuticallyacceptable salt thereof, as defined hereinbefore.

According to a further aspect of the specification, there is provided acompound of the Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH),(IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, asdefined hereinbefore, for use in the prevention or treatment of cancerin a warm-blooded animal such as man.

According to a further aspect of the specification there is provided theuse of a compound of the Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable saltthereof, as defined hereinbefore in the manufacture of a medicament foruse in the prevention or treatment of cancer in a warm-blooded animalsuch as man.

According to a further aspect of the specification there is provided amethod for the prevention or treatment of cancer in a warm-bloodedanimal, such as man, in need of such treatment which comprisesadministering to said animal an effective amount of a compound of theFormula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or(IZA), or a pharmaceutically acceptable salt thereof, as definedhereinbefore.

According to a further aspect of the specification, there is provided acompound of the Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH),(IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, asdefined hereinbefore for use in the prevention or treatment of solidtumour disease in a warm-blooded animal such as man.

According to a further aspect of the specification there is provided theuse of a compound of the Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable saltthereof, as defined hereinbefore, in the manufacture of a medicament foruse in the prevention or treatment of solid tumour disease in awarm-blooded animal such as man.

According to a further aspect of the specification there is provided amethod for the prevention or treatment of solid tumour disease in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof the Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ),(IZ), or (IZA), or a pharmaceutically acceptable salt thereof, asdefined hereinbefore.

According to a further aspect of the specification there is provided acompound of the Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH),(IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, asdefined hereinbefore, for use in the prevention or treatment of thosetumours which are sensitive to inhibition of ERα that are involved inthe signal transduction steps which lead to the proliferation, survival,invasiveness and migratory ability of tumour cells.

According to a further aspect of the specification there is provided theuse of a compound of the Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable saltthereof, as defined hereinbefore, in the manufacture of a medicament foruse in the prevention or treatment of those tumours which are sensitiveto inhibition of ERα that are involved in the signal transduction stepswhich lead to the proliferation, survival, invasiveness and migratoryability of tumour cells.

According to a further aspect of the specification there is provided amethod for the prevention or treatment of those tumours which aresensitive to inhibition of ERα that are involved in the signaltransduction steps which lead to the proliferation, survival,invasiveness and migratory ability of tumour cells which comprisesadministering to said animal an effective amount of a compound of theFormula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or(IZA), or a pharmaceutically acceptable salt thereof, as definedhereinbefore.

According to a further aspect of the specification there is provided acompound of the Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH),(IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, asdefined hereinbefore for use in providing an inhibitory effect on ERα.

According to a further aspect of the specification there is provided theuse of a compound of the Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable saltthereof, as defined hereinbefore in the manufacture of a medicament foruse in providing an inhibitory effect on ERα.

According to a further aspect of the specification there is alsoprovided a method for providing an inhibitory effect on ERα whichcomprises administering an effective amount of a compound of the Formula(I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), ora pharmaceutically acceptable salt thereof, as defined hereinbefore.

According to a further aspect of the specification there is provided acompound of the Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH),(IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, asdefined hereinbefore, for use in providing a selective inhibitory effecton ERα.

According to a further aspect of the specification there is provided theuse of a compound of the Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable saltthereof, as defined hereinbefore, in the manufacture of a medicament foruse in providing a selective inhibitory effect on ERα.

According to a further aspect of the specification there is alsoprovided a method for providing a selective inhibitory effect on ERαwhich comprises administering an effective amount of a compound of theFormula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or(IZA), or a pharmaceutically acceptable salt thereof, as definedhereinbefore.

Described herein are compounds that can bind to ERα ligand bindingdomain and are selective estrogen receptor degraders. In biochemical andcell based assays the compounds of the present specification are shownto be potent estrogen receptor binders and reduce cellular levels of ERαand may therefore be useful in the treatment of estrogen sensitivediseases or conditions (including diseases that have developedresistance to endocrine therapies), i.e. for use in the treatment ofcancer of the breast and gynaecological cancers (including endometrial,ovarian and cervical) and cancers expressing ERα mutated proteins whichmay be de novo mutations or have arisen as a result of treatment with aprior endocrine therapy such as an aromatase inhibitor.

According to a further aspect of the specification there is provided acompound of the Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH),(IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, asdefined hereinbefore, for use in the treatment of breast orgynaecological cancers.

According to a further aspect of the specification there is provided acompound of the Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH),(IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, asdefined hereinbefore, for use in the treatment of cancer of the breast,endometrium, ovary or cervix.

According to a further aspect of the specification there is provided acompound of the Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH),(IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, asdefined hereinbefore, for use in the treatment of cancer of the breast.

According to a further aspect of the specification there is provided acompound of the Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH),(IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, asdefined hereinbefore, for use in the treatment of cancer of the breast,wherein the cancer has developed resistance to one or more otherendocrine therapies.

According to a further aspect of the specification there is provided amethod for treating breast or gynaecological cancers, which comprisesadministering an effective amount of a compound of the Formula (I),(IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or apharmaceutically acceptable salt thereof, as defined hereinbefore.

According to a further aspect of the specification there is provided amethod for treating cancer of the breast, endometrium, ovary or cervix,which comprises administering an effective amount of a compound of theFormula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or(IZA), or a pharmaceutically acceptable salt thereof, as definedhereinbefore.

According to a further aspect of the specification there is provided amethod for treating breast cancer, which comprises administering aneffective amount of a compound of the Formula (I), (IA), (IB), (IC),(ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceuticallyacceptable salt thereof, as defined hereinbefore.

According to a further aspect of the specification there is provided amethod for treating breast cancer, wherein the cancer has developedresistance to one or more other endocrine therapies, which comprisesadministering an effective amount of a compound of the Formula (I),(IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or apharmaceutically acceptable salt thereof, as defined hereinbefore.

According to a further aspect of the specification there is provided theuse of a compound of the Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable saltthereof, as defined hereinbefore, in the manufacture of a medicament foruse in the treatment of breast or gynaecological cancers.

According to a further aspect of the specification there is provided theuse of a compound of the Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable saltthereof, as defined hereinbefore, in the manufacture of a medicament foruse in the treatment of cancer of the breast, endometrium, ovary orcervix.

According to a further aspect of the specification there is provided theuse of a compound of the Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable saltthereof, as defined hereinbefore, in the manufacture of a medicament foruse in the treatment of breast cancer.

According to a further aspect of the specification there is provided theuse of a compound of the Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable saltthereof, as defined hereinbefore, in the manufacture of a medicament foruse in the treatment of breast cancer, wherein the cancer has developedresistance to one or more other endocrine therapies.

In one feature of the specification, the cancer to be treated is breastcancer. In a further aspect of this feature, the breast cancer isEstrogen Receptor+ve (ER+ve). In one embodiment of this aspect, thecompound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ),(IZ), or (IZA), or a pharmaceutically acceptable salt thereof, is dosedin combination with another anticancer agent, such as an anti-hormonalagent as defined herein.

According to a further aspect of the specification there is provided acompound of the Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH),(IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, asdefined hereinbefore, for use in the treatment of ER+ve breast cancer.

According to a further aspect of the specification there is provided amethod for treating ER+ve breast cancer, which comprises administeringan effective amount of a compound of the Formula (I), (IA), (IB), (IC),(ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceuticallyacceptable salt thereof, as defined hereinbefore.

According to a further aspect of the specification there is provided theuse of a compound of the Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable saltthereof, as defined herein before in the manufacture of a medicament foruse in the treatment of ER+ve breast cancer.

The anti-cancer treatment defined herein may be applied as a soletherapy or may involve, in addition to the compounds of thespecification, conventional surgery or radiotherapy or chemotherapy.Such chemotherapy may include one or more of the following categories ofanti-tumour agents:—

(i) other antiproliferative/antineoplastic drugs and combinationsthereof, as used in medical oncology, such as alkylating agents (forexample cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogenmustard, melphalan, chlorambucil, busulphan, temozolomide andnitrosoureas); antimetabolites (for example gemcitabine and antifolatessuch as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed,methotrexate, cytosine arabinoside, and hydroxyurea); antitumourantibiotics (for example anthracyclines like adriamycin, bleomycin,doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C,dactinomycin and mithramycin); antimitotic agents (for example vincaalkaloids like vincristine, vinblastine, vindesine and vinorelbine andtaxoids like taxol and taxotere and polo kinase inhibitors); andtopoisomerase inhibitors (for example epipodophyllotoxins like etoposideand teniposide, amsacrine, topotecan and camptothecin);(ii) antihormonal agents such as antioestrogens (for example tamoxifen,fulvestrant, toremifene, raloxifene, droloxifene and idoxifene),progestogens (for example megestrol acetate), aromatase inhibitors (forexample as anastrozole, letrozole, vorozole and exemestane);(iii) inhibitors of growth factor function and their downstreamsignalling pathways: included are Ab modulators of any growth factor orgrowth factor receptor targets, reviewed by Stern et al. CriticalReviews in Oncology/Haematology, 2005, 54, pp 11-29); also included aresmall molecule inhibitors of such targets, for example kinaseinhibitors—examples include the anti-erbB2 antibody trastuzumab[Herceptin™], the anti-EGFR antibody panitumumab, the anti-EGFR antibodycetuximab [Erbitux, C225] and tyrosine kinase inhibitors includinginhibitors of the erbB receptor family, such as epidermal growth factorfamily receptor (EGFR/erbB1) tyrosine kinase inhibitors such asgefitinib or erlotinib, erbB2 tyrosine kinase inhibitors such aslapatinib, and mixed erb1/2 inhibitors such as afatanib; similarstrategies are available for other classes of growth factors and theirreceptors, for example inhibitors of the hepatocyte growth factor familyor their receptors including c-met and ron; inhibitors of the insulinand insulin growth factor family or their receptors (IGFR, IR)inhibitors of the platelet-derived growth factor family or theirreceptors (PDGFR), and inhibitors of signalling mediated by otherreceptor tyrosine kinases such as c-kit, AnLK, and CSF-1R; also includedare modulators which target signalling proteins in the PI3-kinasesignalling pathway, for example, inhibitors of PI3-kinase isoforms suchas PI3K-α/β/γ and ser/thr kinases such as AKT, mTOR (such as AZD2014),PDK, SGK, PI4K or PIP5K; also included are inhibitors ofserine/threonine kinases not listed above, for example raf inhibitorssuch as vemurafenib, MEK inhibitors such as selumetinib (AZD6244), Ablinhibitors such as imatinib or nilotinib, Btk inhibitors such asibrutinib, Syk inhibitors such as fostamatinib, aurora kinase inhibitors(for example AZD1152), inhibitors of other ser/thr kinases such as JAKs,STATs and IRAK4, and cyclin dependent kinase inhibitors for exampleinhibitors of CDK1, CDK7, CDK9 and CDK4/6 such as palbociclib;iv) modulators of DNA damage signalling pathways, for example PARPinhibitors (e.g. Olaparib), ATR inhibitors or ATM inhibitors;v) modulators of apoptotic and cell death pathways such as Bcl familymodulators (e.g. ABT-263/Navitoclax, ABT-199);(vi) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, [for example the anti-vascularendothelial cell growth factor antibody bevacizumab (Avastin™) and forexample, a VEGF receptor tyrosine kinase inhibitor such as sorafenib,axitinib, pazopanib, sunitinib and vandetanib (and compounds that workby other mechanisms (for example linomide, inhibitors of integrin αvβ3function and angiostatin)];(vii) vascular damaging agents, such as Combretastatin A4;(viii) anti-invasion agents, for example c-Src kinase family inhibitorslike (dasatinib, J. Med. Chem., 2004, 47, 6658-6661) and bosutinib(SKI-606), and metalloproteinase inhibitors like marimastat, inhibitorsof urokinase plasminogen activator receptor function or antibodies toHeparanase];(ix) immunotherapy approaches, including for example ex-vivo and in-vivoapproaches to increase the immunogenicity of patient tumour cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte-macrophage colony stimulating factor, approaches to decreaseT-cell anergy, approaches using transfected immune cells such ascytokine-transfected dendritic cells, approaches usingcytokine-transfected tumour cell lines and approaches usinganti-idiotypic antibodies. Specific examples include monoclonalantibodies targeting PD-1 (e.g. BMS-936558) or CTLA4 (e.g. ipilimumaband tremelimumab);(x) Antisense or RNAi based therapies, for example those which aredirected to the targets listed.(xi) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2,GDEPT (gene-directed enzyme pro-drug therapy) approaches such as thoseusing cytosine deaminase, thymidine kinase or a bacterial nitroreductaseenzyme and approaches to increase patient tolerance to chemotherapy orradiotherapy such as multi-drug resistance gene therapy.

Accordingly, in one embodiment there is provided a compound of Formula(I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), ora pharmaceutically acceptable salt thereof, and an additionalanti-tumour substance for the conjoint treatment of cancer.

According to this aspect of the specification there is provided acombination suitable for use in the treatment of cancer comprising acompound of the Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH),(IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof andanother anti-tumour agent, in particular any one of the anti tumouragents listed under (i)-(xi) above. In particular, the anti-tumour agentlisted under (i)-(xi) above is the standard of care for the specificcancer to be treated; the person skilled in the art will understand themeaning of “standard of care”.

Therefore in a further aspect of the specification there is provided acompound of the Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH),(IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, incombination with another anti-tumour agent, in particular an anti-tumouragent selected from one listed under (i)-(xi) herein above.

In a further aspect of the specification there is provided a compound ofthe Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ),or (IZA), or a pharmaceutically acceptable salt thereof, in combinationwith another anti-tumour agent, in particular an anti-tumour agentselected from one listed under (i) above.

In a further aspect of the specification there is provided a compound ofthe Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ),or (IZA), or a pharmaceutically acceptable salt thereof, and any one ofthe anti-tumour agents listed under (i) above.

In a further aspect of the specification there is provided a combinationsuitable for use in the treatment of cancer comprising a compound of theFormula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or(IZA), or a pharmaceutically acceptable salt thereof, and a taxoid, suchas for example taxol or taxotere, conveniently taxotere.

In a further aspect of the specification there is provided a compound ofthe Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ),or (IZA), or a pharmaceutically acceptable salt thereof, in combinationwith another anti-tumour agent, in particular an anti-tumour agentselected from one listed under (ii) herein above.

In a further aspect of the specification there is provided a combinationsuitable for use in the treatment of cancer comprising a compound of theFormula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or(IZA), or a pharmaceutically acceptable salt thereof, and any one of theantihormonal agents listed under (ii) above, for example any one of theanti-oestrogens listed in (ii) above, or for example an aromataseinhibitor listed in (ii) above.

In a further aspect of the specification there is provided a combinationsuitable for use in the treatment of cancer comprising a compound of theFormula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or(IZA), or a pharmaceutically acceptable salt thereof, and an mTORinhibitor, such as AZD2014.

In a further aspect of the specification there is provided a combinationsuitable for use in the treatment of cancer comprising a compound of theFormula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or(IZA), or a pharmaceutically acceptable salt thereof, and aPI3Kα-inhibitor, such as the compound1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one,or a pharmaceutically-acceptable salt thereof.

In a further aspect of the specification there is provided a combinationsuitable for use in the treatment of cancer comprising a compound of theFormula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or(IZA), or a pharmaceutically acceptable salt thereof, and a CDK4/6inhibitor, such as palbociclib.

In one aspect the above combination of a compound of the Formula (I),(IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or apharmaceutically acceptable salt thereof, with an anti-tumour agentlisted in (ii) above, or an mTOR inhibitor (such as AZD2014), or aPI3K-α inhibitor (such as the compound1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one)or a CDK4/6 inhibitor (such as palbociclib), is suitable for use in thetreatment of breast or gynaecological cancers, such as cancer of thebreast, endometrium, ovary or cervix, particularly breast cancer, suchas ER+ve breast cancer.

Herein, where the term “combination” is used it is to be understood thatthis refers to simultaneous, separate or sequential administration. Inone aspect of the specification “combination” refers to simultaneousadministration. In another aspect of the specification “combination”refers to separate administration. In a further aspect of thespecification “combination” refers to sequential administration. Wherethe administration is sequential or separate, the delay in administeringthe second component should not be such as to lose the beneficial effectof the combination. Where a combination of two or more components isadministered separately or sequential, it will be understood that thedosage regime for each component may be different to and independent ofthe other components. Conveniently, the compounds of the presentspecification are dosed once daily.

According to a further aspect of the specification there is provided apharmaceutical composition which comprises a compound of Formula (I),(IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or apharmaceutically acceptable salt thereof in combination with ananti-tumour agent selected from one listed under (i)-(xi) herein above,in association with a pharmaceutically acceptable excipient.

According to a further aspect of the specification there is provided apharmaceutical composition which comprises a compound of Formula (I),(IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or apharmaceutically acceptable salt thereof in combination with any one ofantihormonal agents listed under (ii) above, for example any one of theanti-oestrogens listed in (ii) above, or for example an aromataseinhibitor listed in (ii) above in association with a pharmaceuticallyacceptable excipient.

In a further aspect of the specification there is provided apharmaceutical composition comprising a compound of the Formula (I),(IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or apharmaceutically acceptable salt thereof, and an mTOR inhibitor, such asAZD2014, in association with a pharmaceutically acceptable excipient.

In a further aspect of the specification there is provided apharmaceutical composition comprising a compound of the Formula (I),(IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or apharmaceutically acceptable salt thereof, and a PI3Kα-inhibitor, such asthe compound1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one,in association with a pharmaceutically acceptable excipient.

In a further aspect of the specification there is provided apharmaceutical composition comprising a compound of the Formula (I),(IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or apharmaceutically acceptable salt thereof, and a CDK4/6 inhibitor (suchas palbociclib) in association with a pharmaceutically acceptableexcipient.

According to a further aspect of the specification there is provided apharmaceutical composition which comprises a compound of the Formula(I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), ora pharmaceutically acceptable salt thereof, in combination with ananti-tumour agent selected from one listed under (i)-(xi) herein above,in association with a pharmaceutically acceptable excipient for use intreating cancer.

According to a further aspect of the specification there is provided apharmaceutical composition which comprises a compound of the Formula(I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), ora pharmaceutically acceptable salt thereof, in combination with any oneof antihormonal agents listed under (ii) above, for example any one ofthe anti-oestrogens listed in (ii) above, or for example an aromataseinhibitor listed in (ii) above in association with a pharmaceuticallyacceptable excipient for use in treating cancer.

In a further aspect of the specification there is provided apharmaceutical composition comprising a compound of the Formula (I),(IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or apharmaceutically acceptable salt thereof, and an mTOR inhibitor, such asAZD2014, in association with a pharmaceutically acceptable excipient foruse in treating cancer.

In a further aspect of the specification there is provided apharmaceutical composition comprising a compound of the Formula (I),(IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or apharmaceutically acceptable salt thereof, and a PI3Kα-inhibitor, such asthe compound1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one,in association with a pharmaceutically acceptable excipient for use intreating cancer.

In a further aspect of the specification there is provided apharmaceutical composition comprising a compound of the Formula (I),(IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or apharmaceutically acceptable salt thereof, and a CDK4/6 inhibitor (suchas palbociclib) in association with a pharmaceutically acceptableexcipient for use in treating cancer.

In one aspect the above pharmaceutical compositions of a compound of theFormula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or(IZA), or a pharmaceutically acceptable salt thereof, with ananti-tumour agent listed in (ii) above, or an mTOR inhibitor (such asAZD2014), or a PI3K-α inhibitor (such as the compound1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one)or a CDK4/6 inhibitor (such as palbociclib), is suitable for use in thetreatment of breast or gynaecological cancers, such as cancer of thebreast, endometrium, ovary or cervix, particularly breast cancer, suchas ER+ve breast cancer.

According to another feature of the specification there is provided theuse of a compound of the Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable saltthereof in combination with an anti-tumour agent selected from onelisted under (i)-(xi) herein above, in the manufacture of a medicamentfor use in the treatment of cancer in a warm-blooded animal, such asman.

According to a further aspect of the specification there is provided theuse of a compound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF),(IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable saltthereof in combination with any one of antihormonal agents listed under(ii) above, for example any one of the anti-oestrogens listed in (ii)above, or for example an aromatase inhibitor listed in (ii) above in themanufacture of a medicament for use in the treatment of cancer in awarm-blooded animal, such as man.

In a further aspect of the specification there is provided the use of acompound of the Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH),(IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, incombination with an mTOR inhibitor, such as AZD2014, in the manufactureof a medicament for use in the treatment of cancer in a warm-bloodedanimal, such as man.

In a further aspect of the specification there is provided the use of acompound of the Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH),(IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, incombination with a PI3Kα-inhibitor, such as the compound1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one,in the manufacture of a medicament for use in the treatment of cancer ina warm-blooded animal, such as man.

In a further aspect of the specification there is provided the use acompound of the Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH),(IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, incombination with a CDK4/6 inhibitor (such as palbociclib) in themanufacture of a medicament for use in the treatment of cancer in awarm-blooded animal, such as man.

In one aspect the above uses of a compound of the Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or apharmaceutically acceptable salt thereof, in combination with ananti-tumour agent listed in (ii) above, or an mTOR inhibitor (such asAZD2014), or a PI3K-α inhibitor (such as the compound1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one)or a CDK4/6 inhibitor (such as palbociclib), is suitable for use in themanufacture of a medicament for the treatment of breast orgynaecological cancers, such as cancer of the breast, endometrium, ovaryor cervix, particularly breast cancer, such as ER+ve breast cancer.

Therefore in an additional feature of the specification, there isprovided a method of treating cancer in a warm-blooded animal, such asman, in need of such treatment which comprises administering to saidanimal an effective amount of a compound of the Formula (I), (IA), (IB),(IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or apharmaceutically acceptable salt thereof, in combination with ananti-tumour agent selected from one listed under (i)-(xi) herein above.

According to a further aspect of the specification there is provided amethod of treating cancer in a warm-blooded animal, such as man, in needof such treatment which comprises administering to said animal aneffective amount of a compound of Formula (I), (IA), (IB), (IC), (ID),(IE), (IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptablesalt thereof in combination with any one of antihormonal agents listedunder (ii) above, for example any one of the anti-oestrogens listed in(ii) above, or for example an aromatase inhibitor listed in (ii) above.

In a further aspect of the specification there is provided a method oftreating cancer in a warm-blooded animal, such as man, in need of suchtreatment which comprises administering to said animal an effectiveamount of a compound of the Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable saltthereof, in combination with an mTOR inhibitor, such as AZD2014.

In a further aspect of the specification there provided a method oftreating cancer in a warm-blooded animal, such as man, in need of suchtreatment which comprises administering to said animal an effectiveamount of a compound of the Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable saltthereof, in combination with a PI3Kα-inhibitor, such as the compound1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one.

In a further aspect of the specification there is provided a method oftreating cancer in a warm-blooded animal, such as man, in need of suchtreatment which comprises administering to said animal an effectiveamount of a compound of the Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable saltthereof, in combination with a CDK4/6 inhibitor (such as palbociclib).

In one aspect the above combinations, pharmaceutical compositions, usesand methods of treating cancer, are methods for the treatment of breastor gynaecological cancers, such as cancer of the breast, endometrium,ovary or cervix, particularly breast cancer, such as ER+ve breastcancer.

According to a further aspect of the present specification there isprovided a kit comprising a compound of Formula (I), (IA), (IB), (IC),(ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceuticallyacceptable salt thereof in combination with an anti-tumour agentselected from one listed under (i)-(xi) herein above.

According to a further aspect of the present specification there isprovided a kit comprising a compound of Formula (I), (IA), (IB), (IC),(ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceuticallyacceptable salt thereof in combination with an anti-tumour agentselected from one listed under (i) or (ii) herein above.

According to a further aspect of the present specification there isprovided a kit comprising:

a) a compound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH),(IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof in afirst unit dosage form;b) an anti-tumour agent selected from one listed under (i)-(xi) hereinabove in a second unit dosage form; andc) container means for containing said first and second dosage forms.

According to a further aspect of the present specification there isprovided a kit comprising:

a) a compound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH),(IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof in afirst unit dosage form;b) an anti-tumour agent selected from one listed under (i)-(ii) hereinabove in a second unit dosage form; andc) container means for containing said first and second dosage forms.

According to a further aspect of the present specification there isprovided a kit comprising:

a) a compound of the Formula (I), (IA), (IB), (IC), (ID), (IE), (IF),(IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable saltthereof, in a first unit dosage form;b) an anti-tumour agent selected from an anti-tumour agent listed in(ii) above, an mTOR inhibitor (such as AZD2014), a PI3Kα-inhibitor, suchas the compound1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one,and a CDK4/6 inhibitor, such as palbociclib, in a second unit dosageform; andc) container means for containing said first and second dosage forms.

Combination therapy as described above may be added on top of standardof care therapy typically carried out according to its usual prescribingschedule.

Although the compounds of the Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), are primarily of value as therapeuticagents for use in warm-blooded animals (including man), they are alsouseful whenever it is required to inhibit ER-α. Thus, they are useful aspharmacological standards for use in the development of new biologicaltests and in the search for new pharmacological agents.

Personalised Healthcare

Another aspect of the present specification is based on identifying alink between the status of the gene encoding ERα and potentialsusceptibility to treatment with a compound of Formula (I), (IA), (IB),(IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA). In particular, ERαgene status may indicate that a patient is less likely to respond toexisting hormone therapy (such as aromatase inhibitors), in part atleast because some ERα mutations are though to arise as resistancemechanisms to existing treatments. A SERD, particularly a SERD which canbe administered orally in potentially larger doses without excessiveinconvenience, may then advantageously be used to treat patients withERα mutations who may be resistant to other therapies. This thereforeprovides opportunities, methods and tools for selecting patients fortreatment with a compound of Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), particularly cancer patients. Thepresent specification relates to patient selection tools and methods(including personalised medicine). The selection is based on whether thetumour cells to be treated possess wild-type or mutant ERα gene. The ERαgene status could therefore be used as a biomarker to indicate thatselecting treatment with a SERD may be advantageous. For the avoidanceof doubt, compounds of the Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), as described herein are thought to besimilarly active against wild-type and mutant ERα genes, at least thosemutations in ERα gene identified at the date of filing this application.

There is a clear need for biomarkers that will enrich for or selectpatients whose tumours will respond to treatment with a SERD, such as acompound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ),(IZ), or (IZA). Patient selection biomarkers that identify the patientsmost likely to respond to one agent over another are ideal in thetreatment of cancer, since they reduce the unnecessary treatment ofpatients with non-responding tumours to the potential side effects ofsuch agents.

A biomarker can be described as “a characteristic that is objectivelymeasured and evaluated as an indicator of normal biologic processes,pathogenic processes, or pharmacologic responses to a therapeuticintervention”. A biomarker is any identifiable and measurable indicatorassociated with a particular condition or disease where there is acorrelation between the presence or level of the biomarker and someaspect of the condition or disease (including the presence of, the levelor changing level of, the type of, the stage of, the susceptibility tothe condition or disease, or the responsiveness to a drug used fortreating the condition or disease). The correlation may be qualitative,quantitative, or both qualitative and quantitative. Typically abiomarker is a compound, compound fragment or group of compounds. Suchcompounds may be any compounds found in or produced by an organism,including proteins (and peptides), nucleic acids and other compounds.

Biomarkers may have a predictive power, and as such may be used topredict or detect the presence, level, type or stage of particularconditions or diseases (including the presence or level of particularmicroorganisms or toxins), the susceptibility (including geneticsusceptibility) to particular conditions or diseases, or the response toparticular treatments (including drug treatments). It is thought thatbiomarkers will play an increasingly important role in the future ofdrug discovery and development, by improving the efficiency of researchand development programs. Biomarkers can be used as diagnostic agents,monitors of disease progression, monitors of treatment and predictors ofclinical outcome. For example, various biomarker research projects areattempting to identify markers of specific cancers and of specificcardiovascular and immunological diseases. It is believed that thedevelopment of new validated biomarkers will lead both to significantreductions in healthcare and drug development costs and to significantimprovements in treatment for a wide variety of diseases and conditions.

In order to optimally design clinical trials and to gain the mostinformation from these trials, a biomarker may be required. The markermay be measurable in surrogate and tumour tissues. Ideally these markerswill also correlate with efficacy and thus could ultimately be used forpatient selection.

Thus, the technical problem underlying this aspect of the presentspecification is the identification of means for stratification ofpatients for treatment with a compound of Formula (I), (IA), (IB), (IC),(ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA). The technical problem issolved by provision of the embodiments characterized in the claimsand/or description herein.

Tumours which contain wild type ERα are believed to be susceptible totreatment with a compound of Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), for example as a first-line treatment.Tumours may also respond to treatment with a compound of Formula (I),(IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), as asecond-line, third-line or subsequent therapy and this may be useful, inparticular, where the tumours contain mutant ERα and may thus beresistant to existing therapies such as AIs. A higher dosage of acompound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ),(IZ), or (IZA), may be required in the resistant setting than in wildtype tumours).

The specification provides a method of determining sensitivity of cellsto a compound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH),(IJ), (IZ), or (IZA). The method comprises determining the status of ERαgene in said cells. A cell is defined as sensitive to a compound ofFormula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or(IZA), if it inhibits the increase in cell number in a cell growth assay(either through inhibition of cell proliferation and/or throughincreased cell death). Methods of the specification are useful forpredicting which cells are more likely to respond to a compound ofFormula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or(IZA), by growth inhibition.

A sample “representative of the tumour” can be the actual tumour sampleisolated, or may be a sample that has been further processed, e.g. asample of PCR amplified nucleic acid from the tumour sample.

Definitions

In this Personalised Healthcare section:

“Allele” refers to a particular form of a genetic locus, distinguishedfrom other forms by its particular nucleotide or amino acid sequence.

“Amplification reactions” are nucleic acid reactions which result inspecific amplification of target nucleic acids over non-target nucleicacids. The polymerase chain reaction (PCR) is a well known amplificationreaction.

“Cancer” is used herein to refer to neoplastic growth arising fromcellular transformation to a neoplastic phenotype. Such cellulartransformation often involves genetic mutation.

“Gene” is a segment of DNA that contains all the information for theregulated biosynthesis of an RNA product, including a promoter, exons,introns, and other sequence elements which may be located within 5′ or3′ flanking regions (not within the transcribed portions of the gene)that control expression.

“Gene status” refers to whether the gene is wild type or not (i.e.mutant).

“Label” refers to a composition capable of producing a detectable signalindicative of the presence of the target polynucleotide in an assaysample. Suitable labels include radioisotopes, nucleotide chromophores,enzymes, substrates, fluorescent molecules, chemiluminescent moieties,magnetic particles, bioluminescent moieties, and the like. As such, alabel is any composition detectable by spectroscopic, photochemical,biochemical, immunochemical, electrical, optical or chemical means.

“Non-synonymous variation” refers to a variation (variance) in oroverlapping the coding sequence of a gene that result in the productionof a distinct (altered) polypeptide sequence. These variations may ormay not affect protein function and include missense variants (resultingin substitution of one amino acid for another), nonsense variants(resulting in a truncated polypeptide due to generation of a prematurestop codon) and insertion/deletion variants.

“Synonymous variation” refers to a variation (variance) in the codingsequence of a gene that does not affect sequence of the encodedpolypeptide. These variations may affect protein function indirectly(for example by altering expression of the gene), but, in the absence ofevidence to the contrary, are generally assumed to be innocuous.

“Nucleic acid” refers to single stranded or double stranded DNA and RNAmolecules including natural nucleic acids found in nature and/ormodified, artificial nucleic acids having modified backbones or bases,as are known in the art.

“Primer” refers to a single stranded DNA oligonucleotide sequencecapable of acting as a point of initiation for synthesis of a primerextension product which is complementary to the nucleic acid strand tobe copied. The length and sequence of the primer must be such that theyare able to prime the synthesis of extension products. A typical primercontains at least about 7 nucleotides in length of a sequencesubstantially complementary to the target sequence, but somewhat longerprimers are preferred. Usually primers contain about 15-26 nucleotides,but longer or shorter primers may also be employed.

“Polymorphic site” is a position within a locus at which at least twoalternative sequences are found in a population.

“Polymorphism” refers to the sequence variation observed in anindividual at a polymorphic site. Polymorphisms include nucleotidesubstitutions, insertions, deletions and microsatellites and may, butneed not, result in detectable differences in gene expression or proteinfunction. In the absence of evidence of an effect on expression orprotein function, common polymorphisms, including non-synonymousvariants, are generally considered to be included in the definition ofwild-type gene sequence. A catalog of human polymorphisms and associatedannotation, including validation, observed frequencies, and diseaseassociation, is maintained by NCBI (db SNP:http://www.ncbi.nlm.nih.gov/projects/SNP/). Please note that the term“polymorphism” when used in the context of gene sequences should not beconfused with the term “polymorphism” when used in the context of solidstate form of a compound that is the crystalline or amorphous nature ofa compound. The skilled person will understand the intended meaning byits context.

“Probe” refers to single stranded sequence-specific oligonucleotideswhich have a sequence that is exactly complementary to the targetsequence of the allele to be detected.

“Response” is defined by measurements taken according to ResponseEvaluation Criteria in Solid Tumours (RECIST) involving theclassification of patients into two main groups: those that show apartial response or stable disease and those that show signs ofprogressive disease.

“Stringent hybridisation conditions” refers to an overnight incubationat 42° C. in a solution comprising 50% formamide, 5×SSC (750 mM NaCl, 75mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5×Denhardt'ssolution, 10% dextran sulfate, and 20 pg/mL denatured, sheared salmonsperm DNA, followed by washing the filters in 0.1×SSC at about 65° C.

“Survival” encompasses a patients' overall survival and progression-freesurvival.

“Overall survival” (OS) is defined as the time from the initiation ofdrug administration to death from any cause. “Progression-free survival”(PFS) is defined as the time from the initiation of drug administrationto first appearance of progressive disease or death from any cause.

According to one aspect of the specification there is provided a methodfor selecting a patient for treatment with a compound of Formula (I),(IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), themethod comprising providing a tumour cell containing sample from apatient; determining whether the ERα gene in the patient's tumour cellcontaining sample is wild type or mutant; and selecting a patient fortreatment with a compound of Formula (I), (IA), (IB), (IC), (ID), (IE),(IF), (IH), (IJ), (IZ), or (IZA), based thereon.

The method may include or exclude the actual patient sample isolationstep. Thus, according to one aspect of the specification there isprovided a method for selecting a patient for treatment with a compoundof Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or(IZA), the method comprising determining whether the ERα gene in atumour cell containing sample previously isolated from the patient iswild type or mutant; and selecting a patient for treatment with acompound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ),(IZ), or (IZA), based thereon.

In one embodiment, the patient is selected for treatment with a compoundof Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or(IZA), if the tumour cell DNA has a mutant ERα gene. In otherembodiments, a patient whose tumour cell DNA possesses a wild type ERαgene is selected for treatment with a compound of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA).

For the purpose of this specification, a gene status of wild-type ismeant to indicate normal or appropriate expression of the gene andnormal function of the encoded protein. In contrast, mutant status ismeant to indicate expression of a protein with altered function,consistent with the known roles of mutant ERα genes in cancer (asdescribed herein). Any number of genetic or epigenetic alterations,including but not limited to mutation, amplification, deletion, genomicrearrangement, or changes in methylation profile, may result in a mutantstatus. However, if such alterations nevertheless result in appropriateexpression of the normal protein, or a functionally equivalent variant,then the gene status is regarded as wild-type. Examples of variants thattypically would not result in a functional mutant gene status includesynonymous coding variants and common polymorphisms (synonymous ornon-synonymous). As discussed below, gene status can be assessed by afunctional assay, or it may be inferred from the nature of detecteddeviations from a reference sequence.

In certain embodiments the wild-type or mutant status of the ERα gene isdetermined by the presence or absence of non-synonymous nucleic acidvariations in the genes. Observed non-synonymous variationscorresponding to known common polymorphisms with no annotated functionaleffects do not contribute to a gene status of mutant.

Other variations in the ERα gene that signify mutant status includesplice site variations that decrease recognition of an intron/exonjunction during processing of pre-mRNA to mRNA. This can result in exonskipping or the inclusion of normally intronic sequence in spliced mRNA(intron retention or utilization of cryptic splice junctions). This can,in turn, result in the production of aberrant protein with insertionsand/or deletions relative to the normal protein. Thus, in otherembodiments, the gene has a mutant status if there is a variant thatalters splice site recognition sequence at an intron/exon junction.

For ESR1, reference sequences are available for the gene (GenBankaccession number: NG_008493), mRNA (GenBank accession number:NM_000125), and protein (GenBank accession number: NP_000116 orSwiss-Prot accession: P03372). A person of skill in the art will be ableto determine the ESR1 gene status, i.e. whether a particular ESR1gene iswild type or mutant, based on comparison of DNA or protein sequence withwild type.

It will be apparent that the gene and mRNA sequences disclosed for ERαgene are representative sequences. In normal individuals there are twocopies of each gene, a maternal and paternal copy, which will likelyhave some sequence differences, moreover within a population there willexist numerous allelic variants of the gene sequence. Other sequencesregarded as wild type include those that possess one or more synonymouschanges to the nucleic acid sequence (which changes do not alter theencoded protein sequence), non-synonymous common polymorphisms (e.g.germ-line polymorphisms) which alter the protein sequence but do notaffect protein function, and intronic non-splice-site sequence changes.

There are numerous techniques available to the person skilled in the artto determine the gene status of ERα. The gene status can be determinedby determination of the nucleic acid sequence. This could be via directsequencing of the full-length gene or analysis of specific sites withinthe gene, e.g. commonly mutated sites.

Samples

The patient's sample to be tested for the gene status can be any tumourtissue or tumour-cell containing sample obtained or obtainable from theindividual. The test sample is conveniently a sample of blood, mouthswab, biopsy, or other body fluid or tissue obtained from an individual.Particular examples include: circulating tumour cells, circulating DNAin the plasma or serum, cells isolated from the ascites fluid of ovariancancer patients, lung sputum for patients with tumours within the lung,a fine needle aspirate from a breast cancer patient, urine, peripheralblood, a cell scraping, a hair follicle, a skin punch or a buccalsample.

It will be appreciated that the test sample may equally be a nucleicacid sequence corresponding to the sequence in the test sample, that isto say that all or a part of the region in the sample nucleic acid mayfirstly be amplified using any convenient technique e.g. polymerasechain reaction (PCR), before analysis. The nucleic acid may be genomicDNA or fractionated or whole cell RNA. In particular embodiments the RNAis whole cell RNA and is used directly as the template for labelling afirst strand cDNA using random primers or poly A primers. The nucleicacid or protein in the test sample may be extracted from the sampleaccording to standard methodologies (see Green & Sambrook, Eds.,Molecular Cloning: A Laboratory Manual, (2012, 4th edition, Vol. 1-3,ISBN 9781936113422), Cold Spring Harbor Laboratory Press, Cold SpringHarbor, N.Y.)

The diagnostic methods of the specification can be undertaken using asample previously taken from the individual or patient. Such samples maybe preserved by freezing or fixed and embedded in formalin-paraffin orother media. Alternatively, a fresh tumour cell containing sample may beobtained and used.

The methods of the specification can be applied using cells from anytumour. Suitable tumours for treatment with a compound of Formula (I),(IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), havebeen described hereinbefore.

Methods for Detection of Nucleic Acids

The detection of mutant ERα nucleic acids can be employed, in thecontext of the present specification, to select drug treatment. Sincemutations in these genes occur at the DNA level, the methods of thespecification can be based on detection of mutations or variances ingenomic DNA, as well as transcripts and proteins themselves. It can bedesirable to confirm mutations in genomic DNA by analysis of transcriptsand/or polypeptides, in order to ensure that the detected mutation isindeed expressed in the subject.

It will be apparent to the person skilled in the art that there are alarge number of analytical procedures which may be used to detect thepresence or absence of variant nucleotides at one or more positions in agene. In general, the detection of allelic variation requires a mutationdiscrimination technique, optionally an amplification reaction (such asone based on polymerase chain reaction) and optionally a signalgeneration system. There are a multitude of mutation detectiontechniques available in the art and these may be used in combinationwith a signal generation system, of which there are numerous availablein the art. Many methods for the detection of allelic variation arereviewed by Nollau et al., Clin. Chem., 1997, 43, 1114-1120; AndersonSM. Expert Rev Mol Diagn., 2011, 11, 635-642; Meyerson M. et al., NatRev Genet., 2010, 11, 685-696; and in standard textbooks, for example“Laboratory Protocols for Mutation Detection”, Ed. by U. Landegren,Oxford University Press, 1996 and “PCR”, 2^(nd) Edition by Newton &Graham, BIOS Scientific Publishers Limited, 1997.

As noted above, determining the presence or absence of a particularvariance or plurality of variances in the ERα gene in a patient withcancer can be performed in a variety of ways. Such tests are commonlyperformed using DNA or RNA collected from biological samples, e.g.,tissue biopsies, urine, stool, sputum, blood, cells, tissue scrapings,breast aspirates or other cellular materials, and can be performed by avariety of methods including, but not limited to, PCR, hybridizationwith allele-specific probes, enzymatic mutation detection, chemicalcleavage of mismatches, mass spectrometry or DNA sequencing, includingminisequencing.

Suitable mutation detection techniques include amplification refractorymutation system (ARMS), amplification refractory mutation system linearextension (ALEX), competitive oligonucleotide priming system (COPS),Taqman, Molecular Beacons, restriction fragment length polymorphism(RFLP), and restriction site based PCR and fluorescence resonance energytransfer (FRET) techniques.

In particular embodiments the method employed for determining thenucleotide(s) within a biomarker gene is selected from: allele-specificamplification (allele specific PCR)—such as amplification refractorymutation system (ARMS), sequencing, allelic discrimination assay,hybridisation, restriction fragment length polymorphism (RFLP) oroligonucleotide ligation assay (OLA).

In particular embodiments, hybridization with allele specific probes canbe conducted by: (1) allele specific oligonucleotides bound to a solidphase (e.g. glass, silicon, nylon membranes) with the labelled sample insolution, for example as in many DNA chip applications; or, (2) boundsample (often cloned DNA or PCR amplified DNA) and labelledoligonucleotides in solution (either allele specific or short so as toallow sequencing by hybridization). Diagnostic tests may involve a panelof variances, often on a solid support, which enables the simultaneousdetermination of more than one variance. Such hybridization probes arewell known in the art (see, e.g., Green & Sambrook, Eds., MolecularCloning: A Laboratory Manual, (2012, 4th edition, Vol. 1-3, ISBN9781936113422), Cold Spring Harbor Laboratory Press, Cold Spring Harbor,N.Y.) and may span two or more variance sites.

Thus, in one embodiment, the detection of the presence or absence of atleast one mutation provides for contacting ERα nucleic acid containing aputative mutation site with at least one nucleic acid probe. The probepreferentially hybridizes with a nucleic acid sequence including avariance site and containing complementary nucleotide bases at thevariance site under selective hybridization conditions. Hybridizationcan be detected with a detectable label using labels known to oneskilled in the art. Such labels include, but are not limited toradioactive, fluorescent, dye, and enzymatic labels.

In another embodiment, the detection of the presence or absence of atleast one mutation provides for contacting ERα nucleic acid containing aputative mutation site with at least one nucleic acid primer. The primerpreferentially hybridizes with a nucleic acid sequence including avariance site and containing complementary nucleotide bases at thevariance site under selective hybridization conditions.

Oligonucleotides used as primers for specific amplification may carrythe complementary nucleotide base to the mutation of interest in thecentre of the molecule (so that amplification depends on differentialhybridization; see, e.g., Gibbs, et al., 1989. Nucl. Acids Res., 17,2437-248) or at the extreme 3′-terminus of one primer where, underappropriate conditions, mismatch can prevent, or reduce polymeraseextension (see, e.g., Prossner, 1993, Tibtech, 11 238).

In yet another embodiment, the detection of the presence or absence ofat least one mutation comprises sequencing at least one nucleic acidsequence and comparing the obtained sequence with the known wild typenucleic acid sequence.

Alternatively, the presence or absence of at least one mutationcomprises mass spectrometric determination of at least one nucleic acidsequence.

In one embodiment, the detection of the presence or absence of at leastone nucleic acid variance comprises performing a polymerase chainreaction (PCR). The target nucleic acid sequence containing thehypothetical variance is amplified and the nucleotide sequence of theamplified nucleic acid is determined. Determining the nucleotidesequence of the amplified nucleic acid comprises sequencing at least onenucleic acid segment. Alternatively, amplification products can beanalysed using any method capable of separating the amplificationproducts according to their size, including automated and manual gelelectrophoresis, and the like.

Mutations in genomic nucleic acid are advantageously detected bytechniques based on mobility shift in amplified nucleic acid fragments.For instance, Chen et al., Anal Biochem 1996, 239, 61-9, describe thedetection of single-base mutations by a competitive mobility shiftassay. Moreover, assays based on the technique of Marcelino et al.,BioTechniques 1999, 26, 1134-1148 are available commercially.

In a particular example, capillary heteroduplex analysis may be used todetect the presence of mutations based on mobility shift of duplexnucleic acids in capillary systems as a result of the presence ofmismatches.

Generation of nucleic acids for analysis from samples generally requiresnucleic acid amplification. Many amplification methods rely on anenzymatic chain reaction (such as a polymerase chain reaction, a ligasechain reaction, or a self-sustained sequence replication) or from thereplication of all or part of the vector into which it has been cloned.Preferably, the amplification according to the specification is anexponential amplification, as exhibited by for example the polymerasechain reaction.

Many target and signal amplification methods have been described in theliterature, for example, general reviews of these methods in Landegren,U., et al., Science, 1988 242, 229-237 and Lewis, R., GeneticEngineering News 1990, 10, 54-55. These amplification methods can beused in the methods of our specification, and include polymerase chainreaction (PCR), PCR in situ, ligase amplification reaction (LAR), ligasehybridisation, Qβ bacteriophage replicase, transcription-basedamplification system (TAS), genomic amplification with transcriptsequencing (GAWTS), nucleic acid sequence-based amplification (NASBA)and in situ hybridisation. Primers suitable for use in variousamplification techniques can be prepared according to methods known inthe art.

Polymerase Chain Reaction (PCR) PCR is a nucleic acid amplificationmethod described inter alia in U.S. Pat. Nos. 4,683,195 and 4,683,202.PCR consists of repeated cycles of DNA polymerase generated primerextension reactions. The target DNA is heat denatured and twooligonucleotides, which bracket the target sequence on opposite strandsof the DNA to be amplified, are hybridised. These oligonucleotidesbecome primers for use with DNA polymerase. The DNA is copied by primerextension to make a second copy of both strands. By repeating the cycleof heat denaturation, primer hybridisation and extension, the target DNAcan be amplified a million fold or more in about two to four hours. PCRis a molecular biology tool, which must be used in conjunction with adetection technique to determine the results of amplification. Anadvantage of PCR is that it increases sensitivity by amplifying theamount of target DNA by 1 million to 1 billion fold in approximately 4hours. PCR can be used to amplify any known nucleic acid in a diagnosticcontext (Mok et al., Gynaecologic Oncology, 1994, 52: 247-252,).

An allele specific amplification technique such as AmplificationRefractory Mutation System (ARMS™) (Newton et al., Nucleic Acids Res.,1989, 17, 2503-2516) can also be used to detect single base mutations.Under the appropriate PCR amplification conditions a single basemismatch located at the 3′-end of the primer is sufficient forpreferential amplification of the perfectly matched allele (Newton etal., 1989, supra), allowing the discrimination of closely relatedspecies. The basis of an amplification system using the primersdescribed above is that oligonucleotides with a mismatched 3′-residuewill not function as primers in the PCR under appropriate conditions.This amplification system allows genotyping solely by inspection ofreaction mixtures after agarose gel electrophoresis.

Analysis of amplification products can be performed using any methodcapable of separating the amplification products according to theirsize, including automated and manual gel electrophoresis, massspectrometry, and the like.

The methods of nucleic acid isolation, amplification and analysis areroutine for one skilled in the art and examples of protocols can befound, for example, Green & Sambrook, Eds., Molecular Cloning: ALaboratory Manual, (2012, 4th edition, Vol. 1-3, ISBN 9781936113422),Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.)Particularly useful protocol source for methods used in PCRamplification is PCR (Basics: From Background to Bench) by M. J.McPherson, S. G. Mailer, R. Beynon, C. Howe, Springer Verlag; 1stedition (Oct. 15, 2000), ISBN: 0387916008.

The present specification also provides predictive and diagnostic kitscomprising degenerate primers to amplify a target nucleic acid in theERα gene and instructions comprising; amplification protocol andanalysis of the results. The kit may alternatively also comprisebuffers, enzymes, and containers for performing the amplification andanalysis of the amplification products. The kit may also be a componentof a screening, or diagnostic kit comprising other tools such as DNAmicroarrays, or other supports. Preferably, the kit also provides one ormore control templates, such as nucleic acids isolated from normaltissue sample, and/or a series of samples representing differentvariances in the reference genes.

In one embodiment, the kit provides two or more primer pairs, each paircapable of amplifying a different region of the reference (ERα) gene(each region a site of potential variance) thereby providing a kit foranalysis of expression of several gene variances in a biological samplein one reaction or several parallel reactions.

Primers in the kits may be labelled, for example fluorescently labelled,to facilitate detection of the amplification products and consequentanalysis of the nucleic acid variances. The kit may also allow for morethan one variance to be detected in one analysis. A combination kit willtherefore comprise of primers capable of amplifying different segmentsof the reference gene. The primers may be differentially labelled, forexample using different fluorescent labels, so as to differentiatebetween the variances.

In another aspect, the specification provides a method of treating apatient suffering from cancer comprising: determining the mutant or wildtype status of the ERα gene in the patient's tumour cells and if the ERαgene is mutant, administering to the patient an effective amount of acompound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ),(IZ), or (IZA).

As used herein, the terms “effective” and “effectiveness” includes bothpharmacological effectiveness and physiological safety. Pharmacologicaleffectiveness refers to the ability of the treatment to result in adesired biological effect in the patient. Physiological safety refers tothe level of toxicity, or other adverse physiological effects at thecellular, organ and/or organism level (often referred to asside-effects) resulting from administration of the treatment. “Lesseffective” means that the treatment results in a therapeuticallysignificant lower level of pharmacological effectiveness and/or atherapeutically greater level of adverse physiological effects.

According to another aspect of the specification there is provided theuse of a compound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF),(IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable saltthereof to treat a cancer patient whose tumour cells have beenidentified as possessing a mutant ERα gene.

According to another aspect of the specification there is provided acompound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ),(IZ), or (IZA), or a pharmaceutically acceptable salt thereof fortreating cancers with tumour cells identified as harbouring mutant ERαgene.

According to another aspect of the specification there is provided amethod of treating cancers with tumour cells identified as harbouringmutant ERα gene comprising administering an effective amount of acompound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ),(IZ), or (IZA), or a pharmaceutically acceptable salt thereof.

In still further embodiments, the specification relates to apharmaceutical composition comprising a compound of Formula (I), (IA),(IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), for use in theprevention and treatment of cancer with tumour cells identified asharbouring a mutant ERα gene.

For all the aspects above, mutant forms of ERα determined/identified areat all positions across the gene.

For all the aspects above, using tumours such as breast cancer as anexample, particular mutant forms of ERα determined/identified are thoseat positions Ser463Pro, Val543Glu, Leu536Arg, Tyr537Ser, Tyr537Asn andAsp538Gly.

EXAMPLES

The specification will now be illustrated in the following Examples inwhich, generally:

(i) operations were carried out at ambient temperature, i.e. in therange 17 to 25° C. and under an atmosphere of an inert gas such asnitrogen unless otherwise stated;

(ii) evaporations were carried out by rotary evaporation or utilisingGenevac equipment or Biotage v10 evaporator in vacuo and work-upprocedures were carried out after removal of residual solids byfiltration;

(iii) flash chromatography purifications were performed on an automatedTeledyne Isco CombiFlash Rf or Teledyne Isco CombiFlash Companion usingprepacked RediSep Rf Gold Silica Columns (20-40 μm, sphericalparticles), GraceResolv Cartridges (Davisil silica) or Silicyclecartridges (40-63 μm).

(iv) preparative chromatography was performed on a Gilson prep HPLCinstrument with UV collection or via supercritical fluid chromatographyperformed on a Waters Prep 100 SFC-MS instrument with MS- andUV-triggered collection or a Thar MultiGram III SFC instrument with UVcollection;

(v) chiral preparative chromatography was performed on a Gilsoninstrument with UV collection (233 injector/fraction collector, 333 &334 pumps, 155 UV detector) or a Varian Prep Star instrument (2×SD1pumps, 325 UV detector, 701 fraction collector) pump running with Gilson305 injection;

(vi) yields, where present, are not necessarily the maximum attainable;(vii) in general, the structures of end-products of the Formula (I) wereconfirmed by nuclear magnetic resonance (NMR) spectroscopy; NMR chemicalshift values were measured on the delta scale [proton magnetic resonancespectra were determined using a Bruker Avance 500 (500 MHz) or BrukerAvance 400 (400 MHz) instrument]; measurements were taken at ambienttemperature unless otherwise specified; the following abbreviations havebeen used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet;dd, doublet of doublets; ddd, doublet of doublet of doublet; dt, doubletof triplets; bs, broad signal

(viii) in general, end-products of the Formula (I) were alsocharacterised by mass spectroscopy following liquid chromatography (LCMSor UPLC); UPLC was carried out using a Waters UPLC fitted with Waters SQmass spectrometer (Column temp 40, UV=220-300 nm, Mass Spec=ESI withpositive/negative switching) at a flow rate of 1 ml/min using a solventsystem of 97% A+3% B to 3% A to 97% B over 1.50 mins (total runtime withequilibration back to starting conditions etc 1.70 min), where A=0.1%formic acid in water (for acid work) or 0.1% ammonia in water (for basework) B=acetonitrile. For acid analysis the column used was WatersAcquity HSS T3 1.8 μm 2.1×50 mm, for base analysis the column used wasWaters Acquity BEH 1.7 μm 2.1×50 mm; LCMS was carried out using a WatersAlliance HT (2795) fitted with a Waters ZQ ESCi mass spectrometer and aPhenomenex Gemini-NX (50=2.1 mm 5 μm) column at a flow rate of 1.1ml/min 95% A to 95% B over 4 min with a 0.5 min hold. The modifier iskept at a constant 5% C (50:50 acetonitrile:water 0.1% formic acid) or D(50:50 acetonitrile:water 0.1% ammonium hydroxide (0.88 SG) depending onwhether it is an acidic or basic method.

(ix) ion exchange purification was generally performed using a SCX-2(Biotage, Propylsulfonic acid functionalized silica. Manufactured usinga trifunctional silane. Non end-capped) cartridge.

(x) intermediate purity was assessed by thin layer chromatographic, massspectral, HPLC (high performance liquid chromatography) and/or NMRanalysis;

(xi) RockPhos 3^(rd) Generation Precatalyst was sourced from StremChemicals Inc. and from Sigma-Aldrich.

(xii) the following abbreviations have been used:—

-   -   AcOH acetic acid    -   aq. aqueous    -   Brettphos 3^(rd) Generation precatalyst        [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)        methanesulfonate    -   Cbz Benzyloxycarbamate    -   CDCl₃ deutero-chloroform    -   Conc. concentrated    -   DCM dichloromethane    -   DIPEA diisopropylethylamine    -   DMF N,N-dimethylformamide    -   DMSO dimethyl sulfoxide    -   EtOAc ethyl acetate    -   HPLC high performance liquid chromatography    -   MeCN acetonitrile    -   MeOH methanol    -   RockPhos 3rd Generation precatalyst        [(2-Di-tert-butylphosphino-3-methoxy-6-methyl-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2-aminobiphenyl)]palladium(II)        methanesulfonate    -   rt/RT room temperature    -   sat. saturated    -   sol. Solution    -   TBAF Tetra-N-butylammonium fluoride    -   TBDMS tert-butyldimethylsilyl    -   TFA trifluoroacetic acid    -   THF tetrahydrofuran    -   XPhos 2nd generation precatalyst        chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)

Example 13-Fluoro-N-(2-(3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine

2,2,2-Trifluoroacetic acid (0.33 mL, 4.35 mmol) was added to a stirredsolution of tert-butyl(2-(3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)(3-fluoropropyl)carbamate(67 mg, 0.12 mmol) in DCM (3.3 mL) at −5° C. under nitrogen. Theresulting mixture was stirred at −5° C. for 1 hour. Saturated NaHCO₃ (5mL) was added carefully and the mixture was extracted with DCM (3×10mL). The combined organics were dried and concentrated to give the crudeproduct. The crude product was purified by preparative HPLC (WatersSunFire column, 5μ silica, 19 mm diameter, 100 mm length), usingdecreasingly polar mixtures of water (containing 1% NH₃) and MeCN aseluents. Fractions containing the desired compounds were evaporated todryness to give3-fluoro-N-(2-(3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine(35 mg, 63%) as a white solid. ¹H NMR (500 MHz, CDCl₃, 22° C.): 1.16(3H, d), 1.83-1.95 (2H, m), 2.60 (1H, dd), 2.77-2.86 (3H, m), 2.88-3(3H, m), 3.10-3.21 (1H, m), 3.29-3.39 (1H, m), 3.98-4.05 (2H, m), 4.40(1H, dd), 4.48 (1H, t), 4.58 (1H, t), 4.59-4.74 (2H, m), 4.82 (1H, dd),4.97 (1H, s), 6.78-6.83 (2H, m), 6.87 (1H, d), 7.10-7.23 (3H, m),7.27-7.30 (1H, m), 7.54 (1H, d), 7.61 (1H, s). m/z: ES+ [M+H]+ 470.

The tert-butyl(2-(3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)(3-fluoropropyl)carbamateused as starting material was prepared as follows:

Preparation of (3-fluorooxetan-3-yl)methyl trifluoromethanesulfonate

2,6-Lutidine (0.441 mL, 3.79 mmol) was added to a stirred solution of(3-fluorooxetan-3-yl)methanol (335 mg, 3.16 mmol) in anhydrous DCM (15mL) at −10° C. Trifluoromethanesulfonic anhydride (0.560 mL, 3.32 mmol)was then added dropwise via syringe over 3 minutes, and the reaction wasallowed to stir at −10° C. for 40 minutes. The cooling bath was removed,and the solution was washed successively with cold aqueous HCl (1 N; 2×5mL) and saturated aqueous NaHCO₃ (2×5 mL), then dried over MgSO₄,filtered and concentrated under reduced pressure. Drying under vacuumafforded (3-fluorooxetan-3-yl)methyl trifluoromethanesulfonate (431 mg,57%) as a pale yellow oil, which was used without further purification.¹H NMR (300 MHz, CDCl₃, 27° C.) 4.53-4.67 (2H, m), 4.79-4.95 (4H, m).

Preparation of(R)—N-((3-fluorooxetan-3-yl)methyl)-1-(1H-indol-3-yl)propan-2-amine

A solution of (3-fluorooxetan-3-yl)methyl trifluoromethanesulfonate (431mg, 1.81 mmol) in DCM (3 mL) was added dropwise to a stirred solution of(R)-1-(1H-indol-3-yl)propan-2-amine (287 mg, 1.65 mmol) anddiisopropylethylamine (0.345 mL, 1.97 mmol) in DCM (7 mL) at ambienttemperature. The reaction was stirred for 8 hours and then diluted withDCM and washed with water. The phases were separated, and the organiclayer was dried over MgSO₄, filtered, and concentrated under reducedpressure. The resulting residue was purified by flash silicachromatography, elution gradient 30 to 100% EtOAc in hexanes. Productfractions were combined and concentrated under reduced pressure toafford(R)—N-((3-fluorooxetan-3-yl)methyl)-1-(1H-indol-3-yl)propan-2-amine (384mg, 89%) as a colorless gum. ¹H NMR (300 MHz, CDCl₃, 27° C.) 1.12 (3H,d), 2.82 (2H, dd), 2.95-3.07 (3H, m), 3.12 (1H, t), 4.49 (2H, ddd), 4.67(1H, dd), 4.70-4.78 (1H, m), 6.92 (1H, d), 7.05-7.14 (1H, m), 7.18 (1H,td), 7.29 (1H, d), 7.59 (1H, d), 8.34 (1H, br s). m/z: ES+ [M+H]+ 263.

Preparation of(1R,3R)-1-(3-bromophenyl)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

Acetic acid (1.0 mL) was added to a stirred solution of(R)—N-((3-fluorooxetan-3-yl)methyl)-1-(1H-indol-3-yl)propan-2-amine (700mg, 2.67 mmol) and 3-bromobenzaldehyde (311 μL, 2.67 mmol) in toluene(9.3 mL). The resulting mixture was heated to 90° C. and stirred for 16hours.

The mixture was concentrated under reduced pressure and the residue waspartitioned between DCM (50 mL) from 1M NaOH (25 mL). The layers wereseparated and the aqueous layer was extracted with DCM (50 mL). Thecombined organic layers were washed with saturated aqueous sodiumchloride (25 mL), dried over MgSO₄, filtered, and concentrated underreduced pressure. The crude product was purified by flash silicachromatography, elution gradient 0 to 40% EtOAc in heptane. Purefractions were evaporated to dryness to afford(1R,3R)-1-(3-bromophenyl)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(809 mg, 71%) as a white solid. ¹H NMR (500 MHz, CDCl₃, 27° C.): 1.18(3H, d), 2.60 (1H, dd), 2.79 (1H, dd), 2.92 (1H, t), 3.18 (1H, dd),3.23-3.30 (1H, m), 4.37 (1H, dd), 4.69 (2H, ddd), 4.86 (1H, dd), 5.02(1H, s), 7.11-7.23 (4H, m), 7.31 (1H, d), 7.35 (1H, s), 7.40 (1H, dd),7.55 (1H, d), 7.64 (1H, s). m/z: ES+ [M+H]+ 429.

Preparation of tert-butyl 3-fluoropropyl(2-hydroxyethyl)carbamate

A solution of 1-iodo-3-fluoropropane (7.0 g, 37 mmol) in acetonitrile(10 mL) was added to a suspension of ethanolamine (4.50 mL, 74.5 mmol)and potassium carbonate (25.7 g, 186 mmol) in acetonitrile (60 mL). Themixture was stirred at room temperature for 5 hours and then dilutedwith DCM (20 ml). The mixture was cooled to 0° C. and di-tert-butyldicarbonate (19.0 mL, 81.9 mmol) was added. The mixture was stirred atroom temperature for 3 hours and filtered. The filtrate was concentratedunder reduced pressure, and the resulting residue was purified by flashsilica chromatography, elution gradient 0 to 4% methanol in DCM toafford tert-butyl (3-fluoropropyl)(2-hydroxyethyl)carbamate (3.82 g,46%) as a colorless oil. ¹H NMR (300 MHz, DMSO-d₆): 1.4 (9H, s),1.70-2.00 (2H, m), 3.10-3.20 (2H, m), 3.30 (2H, d), 3.50 (2H, d),4.30-4.60 (2H, m), 4.60 (1H, br t). m/z: ES+ [M+Na]+244.

Preparation of tert-butyl(2-(3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)(3-fluoropropyl)carbamate

(1R,3R)-1-(3-bromophenyl)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(100 mg, 0.23 mmol), cesium carbonate (190 mg, 0.58 mmol) and RockPhos3rd generation (19.75 mg, 0.02 mmol) were charged to a flask and theflask was evacuated and back filled with nitrogen 3 times. A solution oftert-butyl (3-fluoropropyl)(2-hydroxyethyl)carbamate (103 mg, 0.47 mmol)in degassed toluene (0.78 mL) was added and the reaction heated to 90°C. for 16 hours. After cooling, the reaction was partitioned betweenwater (20 mL) and EtOAc (20 mL). The layers were separated and theaqueous was extracted with EtOAc (2×20 mL). The combined organic layerswere washed with saturated aqueous sodium chloride (20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography eluting with0-50% ethyl acetate in heptane. Fractions containing product werecombined and concentrated in vacuo to give tert-butyl(2-(3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)(3-fluoropropyl)carbamate(77 mg, 58%) as a white solid. ¹H NMR (500 MHz, CDCl₃, 27° C.): 1.16(3H, d), 1.35-1.51 (9H, m), 1.97 (2H, s), 2.52-2.65 (1H, m), 2.84 (1H,dd), 2.88-2.98 (1H, m), 3.15 (1H, dd), 3.32-3.44 (3H, m), 3.49-3.60 (2H,m), 3.97-4.09 (2H, m), 4.40 (2H, dd), 4.50 (1H, s), 4.57-4.66 (1H, m),4.65-4.73 (1H, m), 4.75-4.84 (1H, m), 4.95 (1H, s), 6.76-6.84 (2H, m),6.86 (1H, d), 7.09-7.18 (2H, m), 7.20 (1H, t), 7.28 (1H, d), 7.53 (1H,d), 7.66 (1H, s). m/z: ES+ [M+H]+ 570.

Example 2N-1-(3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-N-2-(3-fluoropropyl)ethane-1,2-diamine

Benzyl(2-((3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)amino)ethyl)(3-fluoropropyl)carbamate(55 mg, 0.09 mmol) and 10% palladium on carbon (19.4 mg, 0.02 mmol) inethanol (1 mL) were stirred under an atmosphere of hydrogen at 21° C.for 30 minutes. The mixture was diluted with DCM (20 mL) and the solidswere filtered through celite, washing the filtercake with DCM (10 mL).The combined organics were combined and concentrated under reducedpressure to give the crude product. The crude product was purified bypreparative HPLC (Waters SunFire column, 5 silica, 19 mm diameter, 100mm length), using decreasingly polar mixtures of water (containing 1%NH₃) and MeCN as eluents. Fractions containing the desired compoundswere evaporated to dryness to giveN1-(3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-N2-(3-fluoropropyl)ethane-1,2-diamine(25 mg, 59%) as a white solid. ¹H NMR (500 MHz, CDCl₃, 27° C.): 1.15(3H, d), 1.79-1.92 (2H, m), 2.59 (1H, dd), 2.75 (2H, t), 2.82-3.00 (4H,m), 3.06-3.20 (3H, m), 3.36-3.45 (1H, m), 4.05 (1H, s), 4.39-4.49 (2H,m), 4.54-4.64 (2H, m), 4.69 (1H, dd), 4.78 (1H, dd), 4.88 (1H, s),6.51-6.57 (2H, m), 6.62 (1H, d), 7.08-7.18 (3H, m), 7.26 (1H, s), 7.53(1H, d), 7.57 (1H, s). m/z: ES+ [M+H]+ 469.

The benzyl(2-((3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)amino)ethyl)(3-fluoropropyl)carbamateused as starting material was prepared as follows:

Preparation of benzyl(2-((tert-butoxycarbonyl)amino)ethyl)(3-fluoropropyl)carbamate

A solution of 1-iodo-3-fluoropropane (3.52 g, 18.7 mmol) in acetonitrile(5 mL) was added to a suspension of tert-butyl (2-aminoethyl)carbamate(5.0 g, 31 mmol) and potassium carbonate (8.63 g, 62.4 mmol) inacetonitrile (30 mL). The mixture was stirred at room temperature for 3hours and then filtered. The filtrate was concentrated under reducedpressure and then DCM (50 mL) was added. The solution was cooled to 0°C., and DIPEA (7.10 mL, 40.7 mmol) was added followed by slow dropwiseaddition of benzyl chloroformate (4.56 mL, 32.0 mmol). Once addition wascomplete, the ice bath was removed, and the reaction mixture was stirredat room temperature for 6 hours. The reaction was diluted with water andextracted with ethyl acetate. The organic layer was dried over sodiumsulfate, filtered and concentrated under reduced pressure. The resultingresidue was purified by flash silica chromatography, elution gradient 0to 80% ethyl acetate in hexane, to give benzyl(2-((tert-butoxycarbonyl)amino)ethyl)(3-fluoropropyl)carbamate (2.1 g,21%) as an oil. ¹H NMR (300 MHz, DMSO-d₆, 27° C.): 1.37 (9H, s),1.74-1.98 (2H, m), 3.01-3.13 (2H, m), 3.19-3.41 (4H, m), 4.29-4.63 (2H,m), 5.07 (2H, s), 6.88 (1H, br. s), 7.30-7.39 (5H, m).

Preparation of benzyl (2-aminoethyl)(3-fluoropropyl)carbamate

Trifluoroacetic acid (3.48 mL, 45.1 mmol) was added to a solution ofbenzyl (2-((tert-butoxycarbonyl)amino)ethyl)(3-fluoropropyl)carbamate(1.6 g, 4.5 mmol) in DCM (16 mL) and stirred at room temperature for 1hour. The reaction was then concentrated under reduced pressure, dilutedwith ethyl acetate, and washed with saturated aqueous sodiumbicarbonate. The organic layer was dried over sodium sulfate, filteredand, concentrated under reduced pressure to give benzyl(2-aminoethyl)(3-fluoropropyl)carbamate (1.1 g, 98%) as a light yellowsolid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.): 1.73-1.98 (2H, m), 2.88 (2H,br. s), 3.37 (4H, q), 4.45 (2H, dt), 5.09 (2H, s), 6.43 (2H, br. s),7.25-7.49 (5H, m).

Preparation of benzyl(2-((3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)amino)ethyl)(3-fluoropropyl)carbamate

BrettPhos Pd G3 (42.2 mg, 0.05 mmol) was added to a degassed mixture of(1R,3R)-1-(3-bromophenyl)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(200 mg, 0.47 mmol), benzyl (2-aminoethyl)(3-fluoropropyl)carbamate (154mg, 0.61 mmol) and potassium carbonate (129 mg, 0.93 mmol) in THF (4.3mL) at 21° C. The resulting mixture was heated to 70° C. and stirred at70° C. for 16 hours. The mixture was allowed to cool to roomtemperature, concentrated under reduced pressure to give the crudeproduct. The crude product was purified by flash silica chromatography,elution gradient 0 to 80% EtOAc in heptane. Pure fractions wereevaporated to dryness to afford benzyl(2-((3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)amino)ethyl)(3-fluoropropyl)carbamate(110 mg, 39%) as a yellow oil. ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.15 (3H,d), 1.90 (2H, s), 2.59 (1H, dd), 2.81-2.99 (2H, m), 3.04-3.17 (1H, m),3.19-3.61 (8H, m), 4.33-4.62 (4H, m), 4.66-4.91 (3H, m), 5.14 (2H, d),6.32-6.70 (3H, m), 7.07-7.15 (2H, m), 7.23 (1H, d), 7.28-7.39 (6H, m),7.49-7.56 (1H, m), 7.66 (1H, d). m/z: ES+ [M+H]+ 603.

Example 3N-1-(3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-N-2-(3-fluoropropyl)-N-1-methylethane-1,2-diamine

A solution of benzyl(2-((3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)(methyl)amino)ethyl)(3-fluoropropyl)carbamate(55.5 mg, 0.09 mmol) in ethanol (2 mL) was hydrogenated in the H-Cubehydrogenation cell using a 30 mm 10% palladium on carbon cartridge, at21° C., 30 bar and a flow rate of 1 ml/minute for 30 minutes. Themixture was concentrated under reduced pressure to give the crudeproduct. The crude product was purified by preparative HPLC (WatersSunFire column, 5μ silica, 19 mm diameter, 100 mm length), usingdecreasingly polar mixtures of water (containing 1% NH₃) and MeCN aseluents. Fractions containing the desired compounds were evaporated todryness to giveN1-(3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-N2-(3-fluoropropyl)-N1-methylethane-1,2-diamine(1.5 mg, 3%) as a white solid. ¹H NMR (500 MHz, CDCl₃, 27° C.): 1.16(3H, d), 1.74-1.88 (2H, m), 2.60 (1H, dd), 2.70 (2H, t), 2.78 (2H, t),2.87 (1H, dd), 2.91 (3H, s), 2.92-2.99 (1H, m), 3.06-3.18 (1H, m),3.35-3.45 (3H, m), 4.40-4.49 (2H, m), 4.53 (1H, t), 4.60 (1H, dd), 4.69(1H, dd), 4.78 (1H, dd), 4.90 (1H, s), 6.56 (1H, d), 6.67 (1H, dd), 6.75(1H, s), 7.07-7.17 (3H, m), 7.26 (1H, s), 7.52 (1H, d), 7.61 (1H, s).m/z: ES+ [M+H]+ 483.

The benzyl(2-((3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)(methyl)amino)ethyl)(3-fluoropropyl)carbamateused as starting material was prepared as follows:

Preparation of benzyl(2-((3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)(methyl)amino)ethyl)(3-fluoropropyl)carbamate

Iodomethane (6.25 μL, 0.10 mmol) was added to a suspension of potassiumcarbonate (18.9 mg, 0.14 mmol) in a solution of benzyl(2-((3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)amino)ethyl)(3-fluoropropyl)carbamate(55 mg, 0.09 mmol) in DMF (1 mL). The resulting mixture was heated at50° C. for 3 hours. Further iodomethane (6.25 μL, 0.10 mmol) was addedand the mixture was stirred at 50° C. for 16 hours. The mixture wasdiluted with EtOAc (20 mL) and water (10 mL). The layers were separatedand the organic layer was washed with water (2×10 mL) and saturatedaqueous sodium chloride (10 mL). The organic layer was dried andconcentrated to give benzyl(2-((3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)(methyl)amino)ethyl)(3-fluoropropyl)carbamate(56 mg, 100%) as an orange oil, which was used without furtherpurification. m/z: ES+ [M+H]+ 617.

Example 43-Fluoro-N-(2-(3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-4-methoxyphenoxy)ethyl)propan-1-amine

Tert-butyl(2-(3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-4-methoxyphenoxy)ethyl)(3-fluoropropyl)carbamate(220 mg, 0.37 mmol) was dissolved in DCM (3.5 mL) and treated with TFA(0.28 mL, 3.7 mmol) dropwise. The reaction was allowed to stir at roomtemperature for 5 hours and then concentrated under reduced pressure.The resulting residue was dissolved in EtOAc, washed with saturatedaqueous NaHCO₃, dried over sodium sulfate, filtered and concentratedunder reduced pressure. The resulting residue was purified by HPLC(Xbridge C18 column, 5 m silica, 19 mm diameter, 100 mm length, 20mL/min) eluting with 50 to 80% acetonitrile in water containing 0.2%NH₄OH (pH 10) over 6 minutes. Product fractions were combined andconcentrated under reduced pressure to afford3-fluoro-N-(2-(3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-4-methoxyphenoxy)ethyl)propan-1-amine(183 mg, 60%) as a white foam. ¹H NMR (300 MHz, DMSO-d₆, 27° C.): 1.07(3H, d), 1.53-1.79 (3H, m), 2.52-2.60 (2H, m), 2.62-2.89 (4H, m),3.03-3.36 (3H, m), 3.75 (2H, t), 3.80 (3H, s), 4.38-4.74 (4H, m), 4.42(2H, dt), 5.36 (1H, s), 6.13 (1H, d), 6.82 (1H, dd), 6.94 (3H, s),7.16-7.23 (1H, m), 7.43 (1H, d), 10.50 (1H, s). m/z: ES+ [M+H]+ 500.

The tert-butyl(2-(3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-4-methoxyphenoxy)ethyl)(3-fluoropropyl)carbamateused as starting material was prepared as follows:

Preparation of(1R,3R)-1-(5-bromo-2-methoxyphenyl)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

(R)—N-((3-fluorooxetan-3-yl)methyl)-1-(1H-indol-3-yl)propan-2-amine (346mg, 1.32 mmol; prepared according to the procedure of Example 1) and5-bromo-2-methoxybenzaldehyde (265 mg, 1.23 mmol) were dissolved intoluene (6.0 mL). Acetic acid (0.67 mL) was added, and the reaction washeated at 80° C. for 18 hours. The reaction was then diluted with EtOAcand neutralized with saturated aqueous NaHCO₃. The layers wereseparated, and the organic layer was dried over sodium sulfate,filtered, and concentrated under reduced pressure. The resulting residuewas purified by flash silica chromatography, elution gradient 0 to 50%EtOAc in hexanes. Fractions containing the desired product were combinedand concentrated under reduced pressure to give(1R,3R)-1-(5-bromo-2-methoxyphenyl)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(513 mg, 91%) as a light yellow foam. ¹H NMR (300 MHz, DMSO-d₆, 27° C.):1.09 (3H, d), 2.52-2.61 (1H, m) 2.62-2.88 (2H, m), 3.06-3.29 (2H, m),3.87 (3H, s), 4.34-4.79 (4H, m), 5.38 (1H, s), 6.61 (1H, d), 6.94-7.09(3H, m), 7.19-7.27 (1H, m), 7.39-7.51 (2H, m), 10.56 (1H, s). m/z: ES+[M+H]+ 459.

Preparation of tert-butyl(2-(3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-4-methoxyphenoxy)ethyl)(3-fluoropropyl)carbamate

(1R,3R)-1-(5-Bromo-2-methoxyphenyl)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(250 mg, 0.54 mmol), tert-butyl(3-fluoropropyl)(2-hydroxyethyl)carbamate (181 mg, 0.82 mmol), andcesium carbonate (355 mg, 1.09 mmol) were suspended in toluene (3 mL) ina 25 mL oven-dried pear-shaped flask. The suspension was degassed(evacuated and backfilled with nitrogen), and then RockPhos 3^(rd)Generation Precatalyst (18 mg, 0.02 mmol) was added. The reaction wasfitted with a condenser and heated at 90° C. for 3 hours. The mixturewas diluted with water and extracted with EtOAc. The organic layer wasdried over sodium sulfate, filtered and concentrated under reducedpressure. The resulting residue was purified by flash silicachromatography, elution gradient 0 to 50% EtOAc in hexanes. Fractionscontaining the desired product were combined and concentrated underreduced pressure to give tert-butyl(2-(3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-4-methoxyphenoxy)ethyl)(3-fluoropropyl)carbamate(220 mg, 67%) as a yellow foam. ¹H NMR (300 MHz, DMSO-d₆, 27° C.): 1.08(3H, d) 1.17-1.39 (9H, m), 1.61-1.86 (2H, m), 2.53-2.63 (1H, m),2.65-2.90 (2H, m), 3.06-3.30 (4H, m), 3.32-3.45 (2H, m), 3.75-3.90 (5H,m), 4.31 (2H, dt), 4.42-4.76 (4H, m), 5.37 (1H, s), 6.13 (1H, d),6.72-6.91 (1H, m), 6.91-7.10 (3H, m), 7.13-7.28 (1H, m), 7.44 (1H, d),10.50 (1H, s). m/z: ES+ [M+H]+ 600.

Example 53-fluoro-N-(2-(3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-2-methoxyphenoxy)ethyl)propan-1-amine

Tert-butyl(2-(3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-2-methoxyphenoxy)ethyl)(3-fluoropropyl)carbamate(168 mg, 0.28 mmol) was dissolved in DCM (2.5 mL) and treated with TFA(0.22 mL, 2.8 mmol) dropwise. The reaction was stirred at roomtemperature for 2 hours and then concentrated under reduced pressure.The resulting residue was dissolved in EtOAc, washed with saturatedaqueous NaHCO₃, dried over sodium sulfate, filtered, and the filtratewas concentrated under reduced pressure. The resulting residue waspurified by reverse phase HPLC (Xbridge C18 column, 5 μm silica, 19 mmdiameter, 100 mm length, 20 mL/min), eluting with 50 to 80% acetonitrilein water containing 0.2% NH₄OH (pH 10) over 6 minutes. Product fractionswere combined and concentrated under reduced pressure to afford3-fluoro-N-(2-(3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-2-methoxyphenoxy)ethyl)propan-1-amine(63 mg, 45%) as a white foam. ¹H NMR (300 MHz, DMSO-d₆, 27° C.): 1.08(3H, d), 1.67-1.92 (3H, m), 2.52-2.63 (1H, m), 2.63-2.88 (4H, m),2.91-2.99 (2H, br m), 3.07-3.35 (2H, m), 3.85 (3H, s), 3.97-4.12 (2H,m), 4.30-4.70 (6H, m), 5.32 (1H, s), 6.21 (1H, dd), 6.86 (1H, t),6.91-7.07 (3H, m), 7.17-7.26 (1H, m), 7.42 (1H, d), 10.50 (1H, s). m/z:ES+ [M+H]+ 500.

The tert-butyl(2-(3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-2-methoxyphenoxy)ethyl)(3-fluoropropyl)carbamateused as starting material was prepared as follows:

Preparation of(1R,3R)-1-(3-bromo-2-methoxyphenyl)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

(R)—N-((3-Fluorooxetan-3-yl)methyl)-1-(1H-indol-3-yl)propan-2-amine (345mg, 1.32 mmol) and 3-bromo-2-methoxybenzaldehyde (297 mg, 1.38 mmol)were dissolved in toluene (6 mL) and treated with AcOH (0.67 mL). Thereaction was heated at 80° C. for 18 hours and then diluted with ethylacetate. The mixture was washed with saturated aqueous sodiumhydrogencarbonate, the layers were separated, and the organic layer wasdried over sodium sulfate, filtered, and concentrated at reducedpressure. The resulting residue was purified by flash silicachromatography, elution gradient 0 to 50% EtOAc in hexanes. Fractionscontaining desired product were combined and concentrated under reducedpressure to give(1R,3R)-1-(3-bromo-2-methoxyphenyl)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(438 mg, 73%) as a yellow foam. ¹H NMR (300 MHz, DMSO-d₆, 27° C.): 1.11(3H, d) 2.53-2.66 (1H, m) 2.70-2.93 (2H, m) 3.16-3.35 (2H, m) 3.91 (3H,s) 4.33-4.75 (4H, m) 5.36 (1H, s) 6.63 (1H, dd) 6.89-7.09 (3H, m)7.20-7.28 (1H, m) 7.46 (1H, d) 7.56 (1H, dd) 10.59 (1H, s). m/z: ES+[M+H]+ 459.

Preparation of tert-butyl(2-(3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-2-methoxyphenoxy)ethyl)(3-fluoropropyl)carbamate

(1R,3R)-1-(3-bromo-2-methoxyphenyl)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(240 mg, 0.52 mmol), tert-butyl(3-fluoropropyl)(2-hydroxyethyl)carbamate (173 mg, 0.78 mmol; preparedaccording to the procedure of Example 1), and cesium carbonate (340 mg,1.04 mmol) were suspended in toluene (3 mL) in a 25 mL oven-driedpear-shaped flask. The suspension was degassed (evacuation andback-filled with nitrogen) and then treated with RockPhos 3^(rd)Generation Precatalyst (18 mg, 0.02 mmol). The reaction flask was fittedwith a condenser and heated at 90° C. for 3 hrs. The mixture was thendiluted with water and extracted with EtOAc. The organic layer was driedover sodium sulfate, filtered, and concentrated under reduced pressure.The resulting residue was purified by flash silica chromatography,elution gradient 0 to 50% EtOAc in hexanes. Fractions containing desiredproduct were combined and concentrated under reduced pressure to givetert-butyl(2-(3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-2-methoxyphenoxy)ethyl)(3-fluoropropyl)carbamate(168 mg, 54%) as a yellow foam. ¹H NMR (300 MHz, DMSO-d₆, 27° C.): 1.09(3H, d), 1.41 (9H, s), 1.80-1.99 (2H, m), 2.53-2.65 (1H, m), 2.66-2.90(2H, m), 3.10-3.36 (2H, m), 3.42 (2H, t), 3.53-3.70 (2H, m), 3.84 (3H,s), 4.06-4.20 (2H, br m), 4.31-4.72 (6H, m), 5.33 (1H, s), 6.23 (1H,dd), 6.86 (1H, t), 6.92-7.09 (3H, m), 7.17-7.28 (1H, m), 7.39-7.49 (1H,m), 10.52 (1H, s). m/z: ES+ [M+H]+ 600.

Example 6N-(2-(3-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-4-methoxyphenoxy)ethyl)-3-fluoropropan-1-amine

2,2,2-Trifluoroacetic acid (0.5 mL, 0.13 mmol) was added to a solutionof tert-butyl(2-(3-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-4-methoxyphenoxy)ethyl)(3-fluoropropyl)carbamate(76 mg, 0.13 mmol) in DCM (5 mL). The mixture was stirred at roomtemperature for 16 hours. The reaction was concentrated under vacuum,redissolved in MeOH and applied to a pre-wetted (MeOH) SCX-2 cartridge.The cartridge was washed with MeOH (50 mL) and the product eluted with1M NH₃ in MeOH solution (30 mL). The resulting residue was purified bypreparative HPLC (Waters XSelect CSH C18 column, 5μ silica, 30 mmdiameter, 100 mm length), using decreasingly polar mixtures of water(containing 1% NH₃) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness to affordN-(2-(3-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-4-methoxyphenoxy)ethyl)-3-fluoropropan-1-amine(5.0 mg, 8%) as a colourless oil. ¹H NMR (500 MHz, CDCl₃, 27° C.): 1.16(3H, d), 1.77-1.91 (2H, m), 2.55-2.64 (2H, m), 2.69-2.8 (3H, m), 2.88(2H, dd), 2.92-2.98 (1H, m), 2.98-3.09 (1H, m), 3.45-3.53 (1H, m), 3.89(2H, t), 3.92 (3H, s), 4.44 (1H, t), 4.53 (1H, t), 5.29 (1H, s), 5.86(1H, tdd), 6.67 (1H, d), 6.78 (1H, dd), 6.89 (1H, d), 7.07-7.16 (2H, m),7.23 (1H, ddd), 7.49-7.54 (1H, m), 7.69 (1H, s). m/z: ES+ [M+H]+ 476.

The tert-butyl(2-(3-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-4-methoxyphenoxy)ethyl)(3-fluoropropyl)carbamateused as starting material was prepared as follows:

Preparation of 2,2-difluoroethyl trifluoromethanesulfonate

Trifluoromethanesulfonic anhydride (3.97 ml, 23.5 mmol) was addeddropwise to a solution of 2,2-difluoroethan-1-ol (1.75 g, 21.3 mmol) inDCM (40 mL at) at −10° C. (salt/ice bath). Lutidine (2.98 ml, 25.6 mmol)was then added, and the reaction was stirred for 1 hour at −10° C. Thereaction was then quenched with water, and the layers were separated.The organic layer was washed with water and then dried over sodiumsulfate, filtered and concentrated under reduced pressure to afford2,2-difluoroethyl trifluoromethanesulfonate (3.10 g, 67.9%) as acolorless liquid. ¹H NMR (500 MHz, CDCl₃, 27° C.) 4.57 (2H, td), 6.03(1H, tt).

Preparation of (R)—N-(2,2-difluoroethyl)-1-(1H-indol-3-yl)propan-2-amine

(R)-1-(1H-Indol-3-yl)propan-2-amine (5 g, 28.69 mmol) was added to asolution of 2,2-difluoroethyl trifluoromethanesulfonate (7.07 g, 33.00mmol) and DIPEA (7.44 mL, 43.04 mmol) in chloroform (100 mL) and thereaction was stirred at 60° C. for 16 hours. The reaction mixtureallowed to cool and concentrated in vacuo. The crude product waspurified by flash silica chromatography, elution gradient 0 to 40% EtOAcin heptane to afford(R)—N-(2,2-difluoroethyl)-1-(1H-indol-3-yl)propan-2-amine (4.22 g, 62%)as a yellow oil.

¹H NMR (500 MHz, CDCl3, 27° C.): 1.12 (3H, d), 2.73-3.17 (5H, m), 3.47(1H, s), 5.77 (1H, tt), 7.01 (1H, d), 7.06-7.17 (1H, m), 7.17-7.23 (1H,m), 7.3-7.42 (1H, m), 7.59 (1H, d), 8.11 (1H, s). m/z: ES− [M−H]− 237.

Preparation of(1R,3R)-1-(5-bromo-2-methoxyphenyl)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

Acetic acid (1.23 mL) was added to a stirred solution of(R)—N-(2,2-difluoroethyl)-1-(1H-indol-3-yl)propan-2-amine (730 mg, 3.06mmol) and 5-bromo-2-methoxybenzaldehyde (659 mg, 3.06 mmol) in toluene(11 mL). The resulting mixture was heated at 90° C. for 16 hours. Thereaction was cooled to room temperature, concentrated under reducedpressure, redissolved in MeOH and applied to a pre-wetted (MeOH) SCX-2cartridge. The cartridge was washed with MeOH (50 mL) and the producteluted with 1M NH₃ in MeOH solution (50 mL). The filtrate wasconcentrated under reduced pressure. The resulting residue was purifiedby flash silica chromatography, elution gradient 0 to 20% EtOAc inheptane. Product fractions were combined and concentrated under reducedpressure to afford(1R,3R)-1-(5-bromo-2-methoxyphenyl)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(429 mg, 32%) as a white solid. ¹H NMR (500 MHz, CDCl₃, 27° C.): 1.13(3H, d), 2.56 (1H, ddd), 2.61-2.75 (1H, m), 2.89 (1H, ddd), 3.02 (1H,qd), 3.33-3.47 (1H, m), 3.90 (3H, s), 5.25 (1H, s), 5.88 (1H, tdd), 6.81(1H, d), 7.05-7.15 (3H, m), 7.16-7.22 (1H, m), 7.33 (1H, dd), 7.51 (1H,dd), 7.57 (1H, s). m/z: ES− [M−H]− 433.

Preparation of tert-butyl(2-(3-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-4-methoxyphenoxy)ethyl)(3-fluoropropyl)carbamate

RockPhos Pd G3 (11.6 mg, 0.01 mmol) was added to a degassed suspensionof(1R,3R)-1-(5-bromo-2-methoxyphenyl)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(120 mg, 0.28 mmol), tert-butyl(3-fluoropropyl)(2-hydroxyethyl)carbamate (122 mg, 0.55 mmol) and cesiumcarbonate (225 mg, 0.69 mmol) in anhydrous toluene (2.76 mL) and thereaction was heated to 90° C. for 1 hour. The reaction mixture wascooled to room temperature and quenched with water (5 mL), diluted withEtOAc (5 mL) and the layers were separated. The aqueous layer wasextracted with EtOAc (3×5 mL) and the combined organic layers were driedwith MgSO₄, filtered and the filtrate was concentrated under reducedpressure. The resulting residue was purified by flash silicachromatography, elution gradient 0 to 50% EtOAc in heptane. Purefractions were evaporated to dryness to afford tert-butyl(2-(3-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-4-methoxyphenoxy)ethyl)(3-fluoropropyl)carbamate(82 mg, 52%) as a colourless gum. ¹H NMR (500 MHz, CDCl₃, 27° C.): 1.15(3H, d), 1.38 (9H, s), 1.79-1.99 (2H, m), 2.58 (1H, dd), 2.65-2.82 (1H,m), 2.89-3.11 (2H, m), 3.32 (2H, t), 3.4-3.53 (3H, m), 3.84-3.95 (5H,m), 4.22-4.50 (2H, m), 5.27 (1H, s), 5.70-6.01 (1H, m), 6.66 (1H, d),6.76 (1H, dd), 6.88 (1H, d), 7.09 (2H, pd), 7.20 (1H, dd), 7.50 (1H, d),7.80 (1H, s). m/z: ES− [M−H]− 574

Example 73-Fluoro-N-(2-(4-methoxy-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine

To a solution of tert-butyl(3-fluoropropyl)(2-(4-methoxy-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)carbamate(62 mg, 0.10 mmol) in DCM (4 mL) was added trifluoroacetic acid (0.5 mL,0.10 mmol). The mixture was stirred at room temperature for 16 hours.The reaction was concentrated under vacuum, redissolved in MeOH andapplied to a pre-wetted (MeOH) SCX-2 cartridge (5 g). The cartridge waswashed with MeOH (50 mL) and the product eluted with 1M NH₃ in MeOHsolution (30 mL). The resulting residue was purified by preparative HPLC(Waters XSelect CSH C18 column, 5μ silica, 30 mm diameter, 100 mmlength), using decreasingly polar mixtures of water (containing 1% NH₃)and MeCN as eluents. Fractions containing the desired compound wereevaporated to dryness to afford3-fluoro-N-(2-(4-methoxy-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine(17 mg, 33%) as a colourless oil. ¹H NMR (500 MHz, CDCl₃, 27° C.): 1.18(3H, d), 1.77-1.89 (2H, m), 2.60 (1H, ddd), 2.73 (2H, t), 2.86-2.9 (2H,m), 2.92-3.02 (2H, m), 3.24 (1H, dq), 3.61 (1H, td), 3.90 (6H, m), 4.48(2H, dt), 5.36 (1H, s), 6.76-6.81 (2H, m), 6.87-6.92 (1H, m), 7.06-7.15(2H, m), 7.22 (1H, ddd), 7.48-7.54 (1H, m), 7.83 (1H, s). m/z: ES+[M+H]+ 494.

The tert-butyl(3-fluoropropyl)(2-(4-methoxy-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)carbamateused a starting material was prepared as follows:

Preparation of 2,2,2-trifluoroethyl trifluoromethanesulfonate

Trifluoromethanesulfonic anhydride (3.14 mL, 18.6 mmol) was addeddropwise via syringe over 5 minutes to a stirred solution of2,2,2-trifluoroethan-1-ol (1.23 mL, 16.9 mmol) and 2,6-dimethylpyridine(2.36 mL, 20.3 mmol) in DCM (50 mL) at −10° C. After 2 hours thereaction was washed successively with aqueous HCl (1N; 2×30 mL) andsaturated aqueous NaHCO₃ (20 mL). The organic layer was then dried overMgSO₄, filtered, and concentrated under reduced pressure to give2,2,2-trifluoroethyl trifluoromethanesulfonate (0.92 g, 23%) as a redoil. ¹H NMR (300 MHz, CDCl₃, 27° C.): 4.69 (2H, q).

Preparation of(R)-1-(1H-indol-3-yl)-N-(2,2,2-trifluoroethyl)propan-2-amine

2,2,2-Trifluoroethyl trifluoromethanesulfonate (1.91 g, 13.29 mmol) wasadded to a solution of (R)-1-(1H-indol-3-yl)propan-2-amine (2.32 g,13.29 mmol) and DIPEA (3.44 ml, 19.93 mmol) in 1,4-dioxane (30 ml) andthe reaction was stirred at 85° C. for 4 hours. The reaction mixtureallowed to cool and concentrated in vacuo. The crude product waspurified by flash silica chromatography, elution gradient 0 to 40% EtOAcin heptane. Pure fractions were evaporated to dryness to afford(R)-1-(1H-indol-3-yl)-N-(2,2,2-trifluoroethyl)propan-2-amine (2.81 g,83%) as a colourless oil.

¹H NMR (500 MHz, CDCl₃, 27° C.): 1.14 (3H, d), 2.81-2.88 (2H, m),3.11-3.22 (3H, m), 7.06 (1H, d), 7.12 (1H, ddd), 7.21 (1H, ddd), 7.37(1H, dt), 7.60 (1H, ddd), 8.01 (1H, s). m/z: ES− [M−H]− 255.

Preparation of(1R,3R)-1-(5-bromo-2-methoxyphenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

Acetic acid (1.06 mL) was added to a stirred solution of(R)-1-(1H-indol-3-yl)-N-(2,2,2-trifluoroethyl)propan-2-amine (680 mg,2.65 mmol) and 5-bromo-2-methoxybenzaldehyde (571 mg, 2.65 mmol) intoluene (9.55 mL). The resulting mixture was heated at 90° C. for 16hours. The reaction was concentrated under vacuum, redissolved in MeOHand applied to a pre-wetted (MeOH) SCX-2 cartridge (5 g). The cartridgewas washed with MeOH (50 mL) and the product eluted with 1M NH₃ in MeOHsolution (50 mL). The filtrate was concentrated under vacuum. Theresulting residue was purified by flash silica chromatography, elutiongradient 0 to 20% EtOAc in heptane. Pure fractions were evaporated todryness to afford(1R,3R)-1-(5-bromo-2-methoxyphenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(681 mg, 57%) as a colourless gum. ¹H NMR (500 MHz, CDCl₃, 27° C.): 1.17(3H, d), 2.58 (1H, ddd), 2.82-3.01 (2H, m), 3.23 (1H, dq), 3.52 (1H,td), 3.92 (3H, s), 5.36 (1H, s), 6.83 (1H, d), 7.07-7.17 (3H, m),7.19-7.24 (1H, m), 7.34 (1H, dd), 7.49-7.55 (1H, m), 7.68 (1H, s). m/z:ES− [M+H]+ 453

Preparation of tert-butyl(3-fluoropropyl)(2-(4-methoxy-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)carbamate

RockPhos Pd G3 (11.57 mg, 0.01 mmol) was added to a degassed suspensionof(1R,3R)-1-(5-bromo-2-methoxyphenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(125 mg, 0.28 mmol), tert-butyl(3-fluoropropyl)(2-hydroxyethyl)carbamate (122 mg, 0.55 mmol) and cesiumcarbonate (225 mg, 0.69 mmol) in toluene (2.76 mL) and the reaction washeated to 90° C. for 1 hour. The reaction mixture was cooled to roomtemperature and quenched with water (5 mL), diluted with EtOAc (5 mL)and the layers were separated. The aqueous layer was extracted withEtOAc (3×5 mL) and the combined organic layers were dried over MgSO₄,filtered and concentrated under vacuum. The resulting residue waspurified by flash silica chromatography, elution gradient 0 to 50% EtOAcin heptane. Pure fractions were evaporated to dryness to affordtert-butyl(3-fluoropropyl)(2-(4-methoxy-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)carbamate(69.0 mg, 42%) as a colourless oil. ¹H NMR (500 MHz, CDCl₃, 27° C.):1.19 (3H, d), 1.40 (9H, s), 1.81-1.99 (2H, m), 2.61 (1H, dd), 2.89-3.07(2H, m), 3.24 (1H, dq), 3.32-3.39 (2H, m), 3.41-3.57 (2H, m), 3.63 (1H,h), 3.85-3.97 (5H, m), 4.39 (2H, d), 5.35 (1H, s), 6.72-6.83 (2H, m),6.90 (1H, d), 7.04-7.16 (2H, m), 7.2-7.24 (1H, m), 7.46-7.55 (1H, m),7.83 (1H, s). m/z: ES− [M−H]− 592.

Example 82,2-Difluoro-3-((1R,3R)-1-(5-(2-((3-fluoropropyl)amino)ethoxy)-2-methoxyphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propan-1-ol

To a solution of tert-butyl(2-(3-((1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-4-methoxyphenoxy)ethyl)(3-fluoropropyl)carbamate(152 mg, 0.25 mmol) in DCM (4 mL) was added trifluoroacetic acid (0.5mL, 0.25 mmol). The mixture was stirred at room temperature for 16hours. The reaction was concentrated under vacuum, redissolved in MeOHand applied to a pre-wetted (MeOH) SCX-2 cartridge. The cartridge waswashed with MeOH (50 mL) and the product eluted with 1M NH₃ in MeOHsolution (50 mL). The resulting residue was purified by preparative HPLC(Waters XSelect CSH C18 column, 5μ silica, 30 mm diameter, 100 mmlength), using decreasingly polar mixtures of water (containing 1% NH₃)and MeCN as eluents. Fractions containing the desired compound wereevaporated to dryness to afford2,2-difluoro-3-((1R,3R)-1-(5-(2-((3-fluoropropyl)amino)ethoxy)-2-methoxyphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propan-1-ol(62 mg, 49%) as a colourless oil. ¹H NMR (500 MHz, CDCl₃, 27° C.): 1.18(3H, d), 1.74-1.88 (2H, m), 2.58-2.67 (1H, m), 2.70 (2H, t), 2.79-3 (4H,m), 3.08-3.23 (1H, m), 3.57-3.81 (3H, m), 3.82-3.91 (6H, m), 4.04 (1H,s), 4.41 (1H, t), 4.50 (1H, t), 5.35 (1H, s), 6.60 (1H, d), 6.79 (1H,dd), 6.86 (1H, d), 7.06-7.15 (2H, m), 7.15-7.22 (1H, m), 7.45-7.58 (1H,m), 7.87 (1H, s). m/z: ES+ [M+H]+ 506.

The tert-butyl(2-(4-((1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenoxy)ethyl)(3-fluoropropyl)carbamateused as starting material was prepared as follows:

Preparation of 3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropan-1-ol

NaH in mineral oil (60 wt %; 343 mg, 8.58 mmol) was added in one portionto a stirred solution of 2,2-difluoropropane-1,3-diol (874 mg, 7.80mmol) in THF (32 mL) at 0° C. The reaction was allowed to warm to roomtemperature, and was stirred at room temperature for 2 hours. Thereaction mixture was again cooled to 0° C., andtert-butyldiphenylchlorosilane (2.0 mL, 7.8 mmol) was added dropwise viasyringe. The reaction mixture was allowed to warm to room temperatureover 1 hour and was then quenched with water and extracted with EtOAc.The organic layer was dried with Na₂SO₄, filtered, and the filtrate wasconcentrated under reduced pressure. The resulting residue was purifiedby flash silica chromatography, eluting to with isocratic 5% ethylacetate in hexanes, to afford3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropan-1-ol (1.94, 71%) asa colorless oil. ¹H NMR (300 MHz, CDCl₃, 27° C.): 1.03-1.14 (9H, s),3.87-3.93 (4H, m), 7.37-7.44 (6H, m), 7.64-7.66 (4H, m).

Preparation of 3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyltrifluoromethanesulfonate

A solution of 3-((tert-butyldiphenyl silyl)oxy)-2,2-difluoropropan-1-ol(1.94 g, 5.55 mmol) and 2,6-dimethylpyridine (1.94 ml, 16.6 mmol) in DCM(18 ml) was cooled to −10° C. (salt/ice bath). Trifluoromethanesulfonicanhydride (1.88 ml, 11.1 mmol) was added slowly dropwise over 10minutes. The reaction was maintained under these conditions for 2 hours.The reaction was then washed with water, aqueous HCl (1N, 100 mL), andsaturated aqueous sodium bicarbonate. The organic layer was dried overMgSO₄, filtered, and concentrated under reduced pressure to afford3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyltrifluoromethanesulfonate (2.68 g, 100%) as a red oil. ¹H NMR (300 MHz,CDCl₃, 27° C.): 1.03-1.14 (9H, s), 3.90 (2H, t), 4.76 (2H, t), 7.39-7.56(6H, m), 7.59-7.75 (4H, m).

Preparation of(R)—N-(1-(1H-indol-3-yl)propan-2-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropan-1-amine

3-((Tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyltrifluoromethanesulfonate (481 mg, 1.00 mmol) was added to a stirredsolution of (R)-1-(1H-indol-3-yl)propan-2-amine (174 mg, 1.00 mmol) in1,4-dioxane (3 mL), followed by DIPEA (0.244 mL, 1.40 mmol). Thereaction was stirred at 85° C. for 5 hours. The reaction was poured intoa mixture of DCM and saturated aqueous sodium bicarbonate. The organiclayer was dried over sodium sulfate, filtered, and concentrated. Theresulting residue was purified by flash silica chromatography, elutiongradient 0 to 35% ethyl acetate in hexanes, to yield(R)—N-(1-(1H-indol-3-yl)propan-2-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropan-1-amine(465 mg, 92%). m/z: ES+ [M+H]+ 507.

Preparation of(1R,3R)-1-(5-bromo-2-methoxyphenyl)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

Acetic acid (545 μL) was added to a stirred solution of(R)—N-(1-(1H-indol-3-yl)propan-2-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropan-1-amine (690 mg, 1.36 mmol) and5-bromo-2-methoxybenzaldehyde (293 mg, 1.36 mmol) in toluene (4.90 mL).The reaction mixture was heated to 90° C. for 16 hours. The reactionmixture was cooled to room temperature and concentrated under vacuum,redissolved in MeOH and applied to a pre-wetted (MeOH) SCX-2 cartridge.The cartridge was washed with MeOH (50 mL) and the product eluted with1M NH₃ in MeOH solution (50 mL). The filtrate was concentrated undervacuum. The resulting residue was purified by flash silicachromatography, elution gradient 0 to 40% EtOAc in heptane. Purefractions were evaporated to dryness to afford(1R,3R)-1-(5-bromo-2-methoxyphenyl)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(395 mg, 41%) as a white solid. ¹H NMR (500 MHz, CDCl₃, 27° C.): 0.96(9H, s), 1.12 (3H, d), 2.50 (1H, ddd), 2.67-2.79 (2H, m), 3.16 (1H,ddd), 3.38-3.47 (1H, m), 3.61-3.71 (4H, m), 3.96 (1H, dt), 5.33 (1H, s),6.66 (1H, d), 6.99-7.07 (2H, m), 7.08 (1H, d), 7.14 (1H, dt), 7.25 (5H,tt), 7.29-7.35 (2H, m), 7.4-7.46 (1H, m), 7.52-7.59 (4H, m), 7.73 (1H,s). m/z: ES+ [M+H]+ 703.

Preparation of tert-butyl(2-(3-((1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-4-methoxyphenoxy)ethyl)(3-fluoropropyl)carbamate

RockPhos Pd G3 (22.66 mg, 0.03 mmol) was added to a degassed suspensionof(1R,3R)-1-(5-bromo-2-methoxyphenyl)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(380 mg, 0.54 mmol), tert-butyl(3-fluoropropyl)(2-hydroxyethyl)carbamate (239 mg, 1.08 mmol) and cesiumcarbonate (440 mg, 1.35 mmol) in toluene (5.4 mL) and the reaction washeated to 90° C. for 1 hour. The reaction mixture was cooled to roomtemperature and quenched with water (5 mL), diluted with EtOAc (5 mL)and the layers were separated. The aqueous layer was extracted withEtOAc (3×5 mL) and the combined organic layers were dried over MgSO₄,filtered and concentrated under vacuum. A solution of 1.0 M TBAF in THF(10 mL) was added and left to stir for 30 min. The reaction mixture wasquenched with water (10 mL), diluted with EtOAc (10 mL) and the layerswere separated. The aqueous layer was extracted with EtOAc (3×10 mL) andthe combined organic layers were dried over MgSO₄, filtered andconcentrated under vacuum. The resulting residue was purified by flashsilica chromatography, elution gradient 0 to 50% EtOAc in heptane. Purefractions were evaporated to dryness to afford tert-butyl(2-(3-((1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-4-methoxyphenoxy)ethyl)(3-fluoropropyl)carbamate(160 mg, 49%) as a colourless oil. ¹H NMR (500 MHz, CDCl₃, 27° C.): 1.21(3H, d), 1.39 (9H, s), 1.8-1.99 (2H, m), 2.65 (1H, dd), 2.86-3.03 (2H,m), 3.12-3.25 (1H, m), 3.3-3.37 (2H, m), 3.42-3.57 (2H, m), 3.62-3.83(4H, m), 3.84-4.03 (5H, m), 4.34 (1H, s), 4.44 (1H, s), 5.35 (1H, s),6.62 (1H, d), 6.81 (1H, dd), 6.90 (1H, d), 7.07-7.17 (2H, m), 7.21-7.25(1H, m), 7.5-7.54 (1H, m), 7.68 (1H, s). m/z: ES+ [M+H]+ 606.

Example 9 Preparation ofN-(2-(2,4-difluoro-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)-3-fluoropropan-1-amine

A solution of tert-butyl(2-(2,4-difluoro-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)(3-fluoropropyl)carbamate(0.30 g, 0.50 mmol) in formic acid (4 mL, 104 mmol) was stirred at roomtemperature for 24 hours and then concentrated under reduced pressure.The resulting residue was taken up in dichloromethane and washed withsaturated aqueous sodium hydrogencarbonate, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The resultingresidue was purified by flash silica chromatography, elution gradient 0to 10% methanol in dichloromethane. Product fractions were combined andconcentrated under reduced pressure to afford a yellow foam solid (131mg). The material was further purified by preparative SFC (column:CHIRALPAK IG, 5 m, 21.2 mm diameter, 250 mm length, 5 mL/min flow rate),eluting with isocratic 20% methanol (containing 0.2% NH₄OH) in CO₂, togiveN-(2-(2,4-difluoro-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)-3-fluoropropan-1-amine(0.080 g, 32%) as a pale yellow solid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.)1.13 (3H, d), 1.67-1.84 (3H, m), 2.57-2.70 (3H, m), 2.74-2.79 (3H, m),2.92-3.11 (1H, m), 3.35-3.67 (2H, m), 4.03 (2H, t), 4.47 (2H, dt), 5.31(1H, s), 6.93-7.05 (3H, m), 7.14-7.23 (2H, m), 7.42 (1H, d), 10.64 (1H,s). m/z: ES+ [M+H]+ 500.

Procedures used to prepare the starting material tert-butyl(2-(2,4-difluoro-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)(3-fluoropropyl)carbamateare described below.

Preparation of(1R,3R)-1-(3-bromo-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

A mixture of(R)-1-(1H-indol-3-yl)-N-(2,2,2-trifluoroethyl)propan-2-amine (0.50 g,1.95 mmol) and 3-bromo-2,6-difluorobenzaldehyde (0.453 g, 2.05 mmol) intoluene (10 mL) and acetic acid (1 mL) was stirred at 100° C. for 5hours. The reaction was then allowed to cool to room temperature and wasconcentrated under reduced pressure. The resulting residue was treatedwith saturated aqueous sodium hydrogencarbonate and extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The resulting residuewas purified by flash silica chromatography, elution gradient 0 to 10%ethyl acetate in hexanes, to give(1R,3R)-1-(3-bromo-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(0.85 g, 95%) as a white foam solid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.)1.13 (3H, d), 2.65 (1H, dd), 2.88 (1H, br dd), 2.93-3.12 (1H, m),3.35-3.47 (1H, m), 3.47-3.67 (1H, m), 5.35 (1H, s), 6.92-7.15 (3H, m),7.22 (1H, d), 7.44 (1H, d), 7.68-7.78 (1H, m), 10.66 (1H, s). m/z: ES+[M+H]+ 459.

Preparation of tert-butyl(2-(2,4-difluoro-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)(3-fluoropropyl)carbamate

A mixture of(1R,3R)-1-(3-bromo-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(0.30 g, 0.65 mmol), tert-butyl(3-fluoropropyl)(2-hydroxyethyl)carbamate (0.289 g, 1.31 mmol), RockPhos3^(rd) Generation Precatalyst (0.027 g, 0.03 mmol) and cesium carbonate(0.532 g, 1.63 mmol) was evacuated and backfilled with nitrogen (3×).Toluene (3.5 mL) was added, and the mixture was again evacuated andbackfilled with nitrogen (2×). The resulting suspension was stirred at90° C. for 2.3 hours and was then cooled to room temperature. Themixture was filtered, and the filtrate was concentrated under reducedpressure. The resulting residue was purified by flash silicachromatography, elution gradient 0 to 30% ethyl acetate in hexanes, togive tert-butyl(2-(2,4-difluoro-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)(3-fluoropropyl)carbamate(0.30 g, 77%) as a pale yellow foam. ¹H NMR (300 MHz, DMSO-d₆, 27° C.)1.03-1.19 (3H, d), 1.34-1.40 (9H, m), 1.71-1.97 (2H, m), 2.63 (1H, dd),2.70-3.13 (2H, m), 3.36-3.63 (4H, m), 4.09 (2H, br t), 4.41 (2H, dt),5.31 (1H, s), 6.88-7.08 (3H, m), 7.13-7.31 (2H, m), 7.42 (1H, d), 10.63(1H, s). (Two hydrogen multiplet obscured by water peak). m/z: ES+[M+H]+ 600.

Example 10 Preparation of3-fluoro-N-(2-(4-fluoro-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine

A solution of tert-butyl(2-(4-fluoro-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)(3-fluoropropyl)carbamate(0.59 g, 1.01 mmol) in formic acid (4 mL, 104 mmol) was stirred at roomtemperature for 24 hours and was then concentrated under reducedpressure. The resulting residue was taken up in dichloromethane andwashed with saturated aqueous sodium hydrogencarbonate, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The resulting residue was purified by flash silicachromatography, elution gradient 0 to 10% methanol in dichloromethane.Product fractions were concentrated under reduced pressure to afford apale yellow foam solid (425 mg). This material was further purified bypreparative SFC (column: CHIRALPAK IG, 5 μm, 21.2 mm diameter, 250 mmlength, 4 mL/min flow rate), eluting with isocratic 15% methanol(containing 0.2% NH₄OH) in CO₂ over, to give3-fluoro-N-(2-(4-fluoro-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine(0.35 g, 71%) as a pale yellow solid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.)1.10 (3H, d), 1.53-1.83 (3H, m), 2.56-2.83 (4H, m), 2.88-3.13 (1H, m),3.14-3.30 (1H, m), 3.44-3.61 (1H, m), 3.81 (2H, brt), 4.42 (2H, dt),5.28 (1H, s), 6.16 (1H, dd), 6.91 (1H, dt), 6.96-7.04 (1H, m), 7.07 (1H,td), 7.17 (1H, t), 7.27 (1H, d), 7.47 (1H, d), 10.70 (1H, s). (Twohydrogen multiplet obscured by DMSO). m/z: ES+, [M+H] 482.

Procedures used to prepare the starting material tert-butyl(2-(4-fluoro-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)(3-fluoropropyl)carbamateare described below.

Preparation of(1R,3R)-1-(5-bromo-2-fluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

A mixture of(R)-1-(1H-indol-3-yl)-N-(2,2,2-trifluoroethyl)propan-2-amine (0.30 g,1.17 mmol) and 5-bromo-2-fluorobenzaldehyde (0.250 g, 1.23 mmol) intoluene (6 mL) and acetic acid (0.67 mL) was stirred at 100° C. for 5hours. The reaction was allowed to cool to room temperature and thenconcentrated under reduced pressure. The resulting residue was basifiedwith saturated aqueous sodium hydrogencarbonate and extracted with ethylacetate. The organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby flash silica chromatography, elution gradient 0 to 10% ethyl acetatein hexanes, to give(1R,3R)-1-(5-bromo-2-fluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(0.51 g, 99%) as a white foam solid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.)1.10 (3H, d), 2.60 (1H, dd), 2.77 (1H, dd), 3.97-3.08 (1H, m), 3.13-3.28(1H, m), 3.40-3.69 (1H, m), 5.31 (1H, s), 6.73 (1H, dd), 6.97-7.04 (1H,m), 7.09 (1H, td), 7.29 (2H, d), 7.49 (1H, d), 7.57 (1H, ddd), 10.71(1H, s). m/z: ES+ [M+H]+ 441.

Preparation of tert-butyl(2-(4-fluoro-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)(3-fluoropropyl)carbamate

A flask containing a mixture of(1R,3R)-1-(5-bromo-2-fluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(0.510 g, 1.16 mmol), tert-butyl(3-fluoropropyl)(2-hydroxyethyl)carbamate (0.511 g, 2.31 mmol), RockPhos3^(rd) Generation Precatalyst (48 mg, 0.060 mmol) and cesium carbonate(0.941 g, 2.89 mmol) was evacuated and backfilled with nitrogen (3×).Toluene (6 mL) was added, and the reaction flask was again evacuated andbackfilled with nitrogen (2×). The resulting suspension was stirred at90° C. for 2.3 hours and then allowed to cool to room temperature. Themixture was filtered, and the filtrate was concentrated under reducedpressure. The resulting residue was purified by flash silicachromatography, elution gradient 0 to 30% ethyl acetate in hexanes, togive tert-butyl(2-(4-fluoro-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)(3-fluoropropyl)carbamate(0.595 g, 89%) as a pale yellow foamy solid. ¹H NMR (300 MHz, DMSO-d₆,27° C.) 1.09 (3H, d), 1.16-1.42 (9H, m), 1.60-1.90 (2H, m), 2.57-2.82(1H, m), 3.01 (1H, br dd), 3.19 (2H, t), 3.22-3.28 (1H, m), 3.34-3.64(3H, m), 3.87 (2H, br t), 4.32 (2H, dt), 5.28 (1H, s), 6.14 (1H, dd),6.86-6.96 (1H, br m), 6.96-7.02 (1H, m), 7.06 (1H, td), 7.17 (1H, t),7.26 (1H, d), 7.47 (1H, d), 10.67 (1H, s). m/z: ES+ [M+H]+ 582.

Example 11 Preparation of3-fluoro-N-(2-(2-fluoro-4-methoxy-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine

A solution of tert-butyl(2-(2-fluoro-4-methoxy-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)(3-fluoropropyl)carbamate(0.21 g, 0.34 mmol) in formic acid (4.0 mL, 104 mmol) was stirred atroom temperature for 20 hours and then concentrated under reducedpressure. The resulting residue was taken up in dichloromethane andwashed with saturated aqueous sodium hydrogencarbonate, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The resulting residue was purified by flash silicachromatography, elution gradient 0 to 10% methanol in dichloromethane.Product fractions were concentrated under reduced pressure to afford ayellow foam solid (120 mg). This solid was further purified bypreparative SFC ((S,S) Whelk-O1 column, 5 μm, 21.2 mm diameter, 250 mmlength, 4.0 mL/min flow rate), eluting with isocratic 25% methanol(containing 0.2% NH₄OH) in CO₂, to give3-fluoro-N-(2-(2-fluoro-4-methoxy-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine(0.10 g, 57%) as a pale yellow solid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.)1.10 (3H, d), 1.61-1.81 (3H, m), 2.54-2.67 (3H, m), 2.76 (2H, br t)2.86-3.03 (2H, m), 3.35-3.52 (2H, m), 3.79 (3H, s), 3.85-3.98 (2H, m),4.44 (2H, dt), 5.41 (1H, s), 6.83 (1H, dd), 6.96 (2H, quind), 7.11 (1H,t), 7.15-7.20 (1H, m), 7.35-7.43 (1H, m), 10.45 (1H, s). m/z: ES+ [M+H]+512.

Procedures used to prepare the starting material tert-butyl(2-(2-fluoro-4-methoxy-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)(3-fluoropropyl)carbamateare described below.

Preparation of(1R,3R)-1-(3-bromo-2-fluoro-6-methoxyphenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

A mixture of(R)-1-(1H-indol-3-yl)-N-(2,2,2-trifluoroethyl)propan-2-amine (0.20 g,0.78 mmol) and 3-bromo-2-fluoro-6-methoxybenzaldehyde (0.191 g, 0.820mmol) in toluene (4 mL) and acetic acid (0.44 mL) was stirred at 100° C.for 5 hours. The reaction was then allowed to cool to room temperatureand was concentrated under reduced pressure. The resulting residue wasbasified with saturated aqueous sodium hydrogencarbonate and extractedwith ethyl acetate. The organic layer was dried over sodium sulfate,filtered and concentrated under reduced pressure. The resulting residuewas purified by flash silica chromatography, elution gradient 0 to 10%ethyl acetate in hexanes, to give(1R,3R)-1-(3-bromo-2-fluoro-6-methoxyphenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(0.32 g, 87%) as a white foam solid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.)1.10 (3H, d), 2.62 (1H, dd), 2.72-2.99 (2H, m), 3.38-3.57 (2H, m), 3.86(3H, s), 5.45 (1H, s), 6.92-7.03 (3H, m), 7.15-7.23 (1H, m), 7.37-7.44(1H, m), 7.64 (1H, dd), 10.48 (1H, s). m/z: ES+ [M+H]+ 471.

Preparation of tert-butyl(2-(2-fluoro-4-methoxy-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)(3-fluoropropyl)carbamate

A flask containing a mixture of(1R,3R)-1-(3-bromo-2-fluoro-6-methoxyphenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(0.32 g, 0.68 mmol), tert-butyl(3-fluoropropyl)(2-hydroxyethyl)carbamate (0.225 g, 1.02 mmol), RockPhos3^(rd) Generation Precatalyst (28 mg, 0.030 mmol) and cesium carbonate(0.553 g, 1.70 mmol) was evacuated and backfilled with nitrogen (3×).Toluene (3.5 mL) was added, and the flask was again evacuated andbackfilled with nitrogen (2×). The resulting suspension was stirred at90° C. for 2.3 hours and then allowed to cool to room temperature. Themixture was filtered, and the filtrate was concentrated under reducedpressure. The resulting residue was purified by flash silicachromatography, elution gradient 0 to 30% ethyl acetate in hexanes, togive tert-butyl(2-(2-fluoro-4-methoxy-3-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)(3-fluoropropyl)carbamate(0.22 g, 52%) as a pale yellow foam solid. ¹H NMR (300 MHz, DMSO-d₆, 27°C.) 1.10 (3H, d), 1.34 (9H, br s), 1.63-1.96 (3H, m), 2.54-2.69 (1H, m),2.87-2.97 (1H, m), 3.18-3.28 (2H, m), 3.46-3.49 (4H, m), 3.78 (3H, s),3.89-4.03 (2H, m), 4.35 (2H, dt), 5.41 (1H, br d), 6.82 (1H, dd), 6.96(2H, quin), 7.12 (1H, t), 7.18 (1H, dd), 7.37-7.41 (1H, m), 10.43 (1H,s). m/z: ES+ [M+H]+ 612.

Example 12 Preparation of3-fluoro-N-(2-((5-methoxy-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-2-yl)oxy)ethyl)propan-1-amine

Trifluoroacetic acid (0.96 mL, 12 mmol) was added to a solution oftert-butyl(3-fluoropropyl)(2-((5-methoxy-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-2-yl)oxy)ethyl)carbamate(370 mg, 0.62 mmol) in DCM (5.2 mL). The mixture was stirred at roomtemperature for 16 hours. Saturated aqueous NaHCO₃ (25 mL) was addedcautiously, and once addition was complete, the mixture was extractedwith DCM (3×50 mL). The combined organic layers were dried over sodiumsulfate, filtered, and concentrated under reduced pressure. Theresulting residue was purified by preparative SFC (column: (S,S)Whelk-O1, 5 μm, 21.2 mm diameter, 250 mm length, 70 mL/min flow rate),eluting with isocratic 25% methanol (containing 0.2% NH₄OH) in CO₂.

Product fractions were concentrated under reduced pressure to give3-fluoro-N-(2-((5-methoxy-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-2-yl)oxy)ethyl)propan-1-amine(109 mg, 35%) as a yellow foamy solid. 1H NMR (300 MHz, DMSO-d₆, 27° C.)1.10 (3H, d), 1.64-1.79 (3H, m), 2.52-2.64 (3H, m), 2.71-2.78 (3H, m),2.93-3.08 (1H, m), 3.22-3.28 (1H, m), 3.44-3.60 (1H, m), 3.90 (3H, s),4.13 (2H, br t), 4.43 (2H, dt), 5.31 (1H, s), 5.92 (1H, s), 6.96-7.03(1H, m), 7.03-7.10 (1H, m), 7.24 (1H, d), 7.45 (1H, d), 7.92 (1H, s),10.61 (1H, s). m/z: ES+ [M+H]+ 495.

Preparation of the starting material tert-butyl(3-fluoropropyl)(2-((5-methoxy-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-2-yl)oxy)ethyl)carbamateis described below.

Preparation of(1R,3R)-1-(2-chloro-5-methoxypyridin-4-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

Acetic acid (1.33 mL) was added to a stirred solution of(R)-1-(1H-indol-3-yl)-N-(2,2,2-trifluoroethyl)propan-2-amine (855 mg,3.34 mmol) and 2-chloro-5-methoxyisonicotinaldehyde (572 mg, 3.34 mmol)in toluene (11.6 mL). The resulting mixture was heated at 90° C. for 5hours. The reaction was then concentrated under vacuum, and theresulting residue was redissolved in dichloromethane. This solution waswashed with saturated aqueous sodium bicarbonate and saturated aqueoussodium chloride and then dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedby flash silica chromatography, eluting with 0 to 75% ethyl acetate inhexanes. Product fractions were concentrated under reduced pressure toafford(1R,3R)-1-(2-chloro-5-methoxypyridin-4-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(1.28 g, 97%) as a colourless gum. ¹H NMR (300 MHz, DMSO-d₆, 27° C.)1.09 (3H, d), 2.60 (1H, dd), 2.80 (1H, dd), 2.90-3.08 (1H, m), 3.19-3.28(1H, m), 3.38-3.63 (1H, m), 3.99 (3H, s), 5.33 (1H, s), 6.54 (1H, s),6.97-7.04 (1H, m) 7.05-7.11 (1H, m), 7.24-7.29 (1H, m), 7.48 (1H, d),8.27 (1H, s), 10.59 (1H, s). m/z: ES+ [M+H]+ 410.

Preparation of tert-butyl(3-fluoropropyl)(2-((5-methoxy-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-2-yl)oxy)ethyl)carbamate

RockPhos 3^(rd) Generation Precatalyst (64.6 mg, 0.08 mmol) was added toa degassed suspension of(1R,3R)-1-(2-bromo-5-methoxypyridin-4-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(350 mg, 0.77 mmol) and cesium carbonate (628 mg, 1.93 mmol) in toluene(7.7 mL) and the reaction was heated at 90° C. for 16 hours. Thereaction mixture was then cooled to room temperature and quenched withwater (15 mL). The mixture was diluted with EtOAc (15 mL), and thelayers were separated. The aqueous layer was extracted with EtOAc (3×15mL), and the combined organic layers were dried over MgSO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby flash silica chromatography, elution gradient 0 to 50% EtOAc inhexane. Product fractions were concentrated under reduced pressure toafford tert-butyl(3-fluoropropyl)(2-((5-methoxy-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-2-yl)oxy)ethyl)carbamate(370 mg, 81%) as a colourless oil. ¹H NMR (300 MHz, DMSO-d₆, 27° C.):1.09 (3H, d), 1.14-1.35 (9H, m), 1.67-1.85 (2H, m), 2.54-2.61 (1H, m),2.69-2.76 (1H, m), 2.96-3.04 (1H, m), 3.17-3.29 (3H, m), 3.35-3.57 (3H,m), 3.90 (3H, s), 4.09-4.25 (2H, m), 4.33 (2H, dt), 5.31 (1H, s), 5.90(1H, s), 6.93-7.09 (2H, m), 7.22-7.26 (1H, m), 7.46 (1H, d), 7.91 (1H,s), 10.58 (1H, s). m/z: ES+ [M+H]+ 595.

Example 13 Preparation ofN-(2-(2,4-difluoro-3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)-3-fluoropropan-1-amine

Formic acid (5 mL) was added to tert-butyl(2-(2,4-difluoro-3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)(3-fluoropropyl)carbamate(0.15 g, 0.25 mmol). The reaction was stirred at room temperature for 2hours and then concentrated under reduced pressure. The resultingresidue was purified via ion-exchange chromatography using an SCX-2cartridge and eluting with ammonia in methanol (3N). Product fractionswere combined and concentrated under reduced pressure. The resultingresidue was further purified by flash silica chromatography, elutiongradient 5 to 10% MeOH in DCM. Product fractions were concentrated underreduced pressure to affordN-(2-(2,4-difluoro-3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)-3-fluoropropan-1-amine(84 mg, 67%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆, 27° C.) 1.10(3H, d), 1.65-1.83 (2H, m), 2.58-2.65 (3H, m), 2.70-2.88 (4H, m),3.17-3.27 (1H, m), 3.33-3.42 (1H, m), 4.01 (2H, t), 4.27 (1H, dd), 4.40(1H, t), 4.42-4.60 (4H, m), 5.27 (1H, s), 6.87-7.03 (3H, m), 7.10-7.22(2H, m), 7.40 (1H, d), 10.60 (1H, s). m/z: ES+ [M+H]+ 506.

Procedures used to prepare the starting material tert-butyl(2-(2,4-difluoro-3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)(3-fluoropropyl)carbamateare described below.

Preparation of(1R,3R)-1-(3-bromo-2,6-difluorophenyl)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

3-Bromo-2,6-difluorobenzaldehyde (0.973 g, 4.40 mmol) was added to asolution of(R)—N-((3-fluorooxetan-3-yl)methyl)-1-(1H-indol-3-yl)propan-2-amine (1.1g, 4.2 mmol) in toluene (18 mL) and acetic acid (2 mL), and the reactionwas heated at 80° C. for 18 hours. The reaction was then concentratedunder reduced pressure, and the resulting residue was dissolved in EtOAcand washed with saturated aqueous NaHCO₃. The organic layer was driedover sodium sulfate, filtered, and concentrated under reduced pressure.The resulting residue was purified by flash silica chromatography,elution gradient 5 to 50% EtOAc in hexane. Product fractions wereconcentrated under reduced pressure to afford(1R,3R)-1-(3-bromo-2,6-difluorophenyl)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(1.4 g, 72%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆, 27° C.) 1.11(3H, d), 2.59 (1H, dd), 2.71-2.85 (2H, m), 3.20-3.29 (1H, m), 3.32-3.39(1H, m), 4.28 (1H, dd), 4.44-4.61 (3H, m), 5.30 (1H, s), 6.93-6.98 (1H,m), 6.99-7.04 (1H, m), 7.05-7.12 (1H, m), 7.20 (1H, d), 7.41 (1H, d),7.74 (1H, td), 10.64 (1H, s). m/z: ES+ [M+H]+ 465.

Preparation of tert-butyl(2-(2,4-difluoro-3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)(3-fluoropropyl)carbamate

Toluene (4.5 mL) was added to a mixture of(1R,3R)-1-(3-bromo-2,6-difluorophenyl)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(0.25 g, 0.54 mmol) and tert-butyl(3-fluoropropyl)(2-hydroxyethyl)carbamate (0.238 g, 1.07 mmol). Thereaction flask was evacuated and backfilled with nitrogen. Cesiumcarbonate (0.438 g, 1.34 mmol) and RockPhos 3^(rd) GenerationPrecatalyst (0.046 g, 0.05 mmol) were added, and the reaction mixturewas again subjected to vacuum and then backfilled with nitrogen. Thereaction was heated at 100° C. for 1 hour before being cooled to roomtemperature and filtered through Celite using a DCM wash. The filtratewas concentrated under reduced pressure, and the resulting residue waspurified by flash silica chromatography, elution gradient 2 to 10% MeOHin DCM. Product fractions were concentrated under reduced pressure toafford tert-butyl(2-(2,4-difluoro-3-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)(3-fluoropropyl)carbamate(151 mg, 46%) as a solid.

¹H NMR (500 MHz, DMSO-d₆, 27° C.) 1.10 (3H, d), 1.33-1.39 (9H, m),1.78-1.89 (2H, m), 2.58 (1H, br dd), 2.72-2.84 (2H, m), 3.18-3.30 (3H,m), 3.34-3.40 (2H, m), 3.45-3.53 (2H, m), 4.07 (2H, br t), 4.28 (1H, brdd), 4.35 (1H, t), 4.42-4.58 (3H, m), 5.27 (1H, s), 6.91-6.97 (2H, m),6.97-7.02 (1H, m), 7.13-7.21 (2H, m), 7.40 (1H, d), 10.60 (1H, s). m/z:ES+ [M+H]+ 606.

Example 143-((1R,3R)-1-(2,6-difluoro-3-(2-((3-fluoropropyl)amino)ethoxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol

tert-Butyl(2-(3-((1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-2,4-difluorophenoxy)ethyl)(3-fluoropropyl)carbamate(0.55 g, 0.90 mmol) was dissolved in formic acid (5 mL). The reactionmixture was heated to 40° C. for 1 hour and the reaction mixtureevaporated. The crude product was purified by flash reverse phase silicachromatography (Puriflash HP C18, 30μ silica, 120 g), using decreasinglypolar mixtures of water (containing 1% NH₃) and MeCN as eluents toafford3-((1R,3R)-1-(2,6-difluoro-3-(2-((3-fluoropropyl)amino)ethoxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-olas a foam (0.230 g, 50%). ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.18 (3H, d),1.82-1.93 (2H, m), 2.68 (1H, ddd), 2.80 (2H, t), 2.83-2.93 (1H, m),2.96-3.01 (2H, m), 3.11 (1H, ddd), 3.25 (1H, dt), 3.61-3.78 (3H, m),4.06-4.12 (2H, m), 4.52 (2H, dt), 5.29 (1H, s), 6.84 (1H, td), 6.96 (1H,td), 7.09-7.16 (2H, m), 7.21-7.24 (1H, m), 7.45 (1H, s), 7.50-7.54 (1H,m) (2H not observed). m/z: ES− [M−H]− 510.

The tert-butyl(2-(3-((1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-2,4-difluorophenoxy)ethyl)(3-fluoropropyl)carbamatewas prepared as follows:

Preparation of(1R,3R)-1-(3-bromo-2,6-difluorophenyl)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

To a solution of(R)—N-(1-(1H-indol-3-yl)propan-2-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropan-1-amine(1.12 g, 2.21 mmol) in toluene (15 mL) and acetic acid (1.67 mL) wasadded 3-bromo-2,6-difluorobenzaldehyde (0.624 g, 2.82 mmol). Thesolution was heated to 90 5° C. and stirred for 16 hours. The reactionmixture was evaporated and the residue was partitioned between DCM and2M NaOH (50 mL each). The organic phase was evaporated and the crudeproduct was purified by flash silica chromatography, elution gradient 0to 25% EtOAc in heptane to afford(1R,3R)-1-(3-bromo-2,6-difluorophenyl)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(1.070 g, 68%) as a white foam. ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.05(9H, s), 1.16 (3H, d), 2.61 (1H, ddd), 2.71-2.81 (1H, m), 2.99 (1H,ddd), 3.25-3.38 (1H, m), 3.57-3.69 (2H, m), 3.91-4.01 (1H, m), 5.36 (1H,s), 6.65-6.71 (1H, m), 7.08-7.16 (2H, m), 7.21-7.25 (1H, m), 7.36-7.44(8H, m), 7.51-7.55 (1H, m), 7.60-7.66 (4H, m).

Preparation of tert-butyl(2-(3-((1R,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-2,4-difluorophenoxy)ethyl)(3-fluoropropyl)carbamate

RockPhos Pd G3 (0.063 g, 0.08 mmol) was added to a degassed suspensionof(1R,3R)-1-(3-bromo-2,6-difluorophenyl)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(1.07 g, 1.51 mmol), tert-butyl(3-fluoropropyl)(2-hydroxyethyl)carbamate (0.667 g, 3.02 mmol) andcesium carbonate (1.23 g, 3.77 mmol) in toluene (15 mL) and the reactionwas heated to 90° C. for 5 hours. The reaction mixture was allowed tocool to room temperature and diluted with water (15 mL). DCM (30 mL) wasadded and the organic phase was separated and evaporated. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 50% EtOAc in heptane to afford tert-butyl(2-(3-((1R,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-2,4-difluorophenoxy)ethyl)(3-fluoropropyl)carbamate(0.850 g, 66%) as a tan foam. ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.04 (9H,s), 1.15 (3H, d), 1.43 (9H, s), 1.84-1.99 (2H, m), 2.60 (1H, dd),2.74-2.85 (1H, m), 3.00 (1H, ddd), 3.23-3.34 (1H, m), 3.35-3.41 (2H, m),3.45-3.62 (3H, m), 3.65-3.72 (1H, m), 3.93-4.09 (3H, m), 4.33-4.49 (2H,m), 5.33 (1H, s), 6.62 (1H, s), 6.77-6.85 (1H, m), 7.07-7.14 (2H, m),7.20-7.23 (1H, m), 7.33-7.44 (6H, m), 7.49-7.52 (1H, m), 7.56 (1H, s),7.58-7.66 (4H, m). m/z: ES+ [M+H]+ 850.

Preparation of tert-butyl(2-(3-((1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-2,4-difluorophenoxy)ethyl)(3-fluoropropyl)carbamate

Tetrabutylammonium fluoride (1.0 M in THF) (1.50 mL, 1.50 mmol) wasadded to a solution of tert-butyl(2-(3-((1R,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-2,4-difluorophenoxy)ethyl)(3-fluoropropyl)carbamate(0.850 g, 1.00 mmol) in tetrahydrofuran (10 mL). The reaction wasstirred at room temp for 90 minutes and then the reaction mixture wasevaporated. The crude product was purified by flash silicachromatography, elution gradient 0 to 80% EtOAc in heptane. Productcontaining fractions were evaporated to dryness to afford tert-butyl(2-(3-((1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-2,4-difluorophenoxy)ethyl)(3-fluoropropyl)carbamate(0.550 g, 90%) as a colourless foam. ¹H NMR (500 MHz, CDCl₃, 27° C.)1.18 (3H, d), 1.44 (9H, s), 1.88-2.02 (2H, m), 2.69 (1H, ddd), 2.83-2.93(1H, m), 3.13 (1H, dd), 3.21-3.32 (2H, m), 3.39-3.44 (2H, m), 3.47-3.79(6H, m), 4.16 (1H, s), 4.45 (2H, dt), 5.28 (1H, s), 6.82 (1H, td), 6.96(1H, s), 7.08-7.15 (2H, m), 7.23 (1H, d), 7.49-7.65 (2H, m). m/z: ES+[M+H]+ 612.

Example 153-((1R,3R)-1-(2,6-difluoro-3-(2-((3-fluoropropyl)amino)ethoxy)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol

TBAF solution (1M in THF) (1.58 mL, 1.58 mmol) was added to tert-butyl(2-(3-((1R,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-2,4-difluorophenoxy)ethyl)(3-fluoropropyl)carbamate(275 mg, 0.32 mmol) and the reaction was stirred at room temperature for1 hour. The reaction was diluted with DCM (10 mL) and washed withsaturated aqueous sodium chloride (10 mL). The aqueous was extractedwith DCM (10 mL), then the combined organics were dried over Na₂SO₄ andevaporated. The crude product was passed through a plug of silica gel,eluting with 1:1 EtOAc/heptane. The fractions containing product wereevaporated to afford crude title compound as a pale yellow gum (˜200mg). The residue was dissolved in formic acid (2 mL) and stirred at 40°C. for 1 hour. The volatiles were evaporated, then the crude product waspurified by preparative HPLC (Waters SunFire column, 5μ silica, 19 mmdiameter, 100 mm length), using decreasingly polar mixtures of water(containing 1% NH₃) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness. The sample was dissolved inMeOH and further purified using the SFC: Column: Phenomenex A1, 30×250mm, 5 micron; Mobile phase: 20% MeOH+0.1% NH₃/80% sc CO₂; Flow rate: 100ml/min; Temperature: 40° C.; BPR: 120 bar, to afford3-((1R,3R)-1-(2,6-difluoro-3-(2-((3-fluoropropyl)amino)ethoxy)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol(72.6 mg, 77%) as a colourless solid. ¹H NMR (500 MHz, CDCl₃, 27° C.)1.18 (3H, d), 1.82-1.95 (2H, m), 2.62 (1H, dd), 2.80 (2H, t), 2.87 (1H,dd), 2.97-3.01 (2H, m), 3.07 (1H, dd), 3.19-3.28 (1H, m), 3.56-3.82 (2H,m), 4.04-4.17 (2H, m), 4.52 (3H, dt), 5.28 (1H, s), 6.82-6.91 (2H, m),6.97 (1H, td), 7.14 (2H, td), 7.43 (1H, s); m/z: ES+ [M+H]+ 530.

The tert-butyl(2-(3-((1R,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-2,4-difluorophenoxy)ethyl)(3-fluoropropyl)carbamateused as starting material was prepared as follows:

Tert-butyl (R)-(1-(5-fluoro-1H-indol-3-yl)propan-2-yl)carbamate

5-fluoro-1H-indole (9.34 g, 69.11 mmol) was dissolved in DCM (470 ml)and cooled to −78° C. Methylmagnesium bromide solution (23.50 mL, 70.50mmol) was added dropwise over 10 min, then tert-butyl(R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (6.56 g,27.65 mmol) in DCM (15 mL) was added dropwise. The reaction was stirredat −78° C. for 30 min, then allowed to warm to 0° C. over 2 hours.Ice-cold 1M aqueous citric acid solution was added (80 mL) and thebiphasic mixture was stirred for 10 min. The layers were separated, thenthe aqueous layer was extracted with DCM (2×100 mL). The combinedorganics were washed with H₂O (50 mL), saturated aqueous sodium chloride(50 mL) then dried over MgSO₄, filtered and concentrated. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 50% EtOAc in heptane. Pure fractions were evaporated to dryness toafford tert-butyl (R)-(1-(5-fluoro-1H-indol-3-yl)propan-2-yl)carbamate(5.56 g, 69%) as a brown solid.

¹H NMR (500 MHz, CDCl₃, 27° C.) 1.12 (3H, d), 1.43 (9H, s), 2.87 (2H,td), 3.93-4.08 (1H, m), 4.36-4.51 (1H, m), 6.93 (1H, td), 7.05 (1H, d),7.23-7.29 (2H, m), 8.11 (1H, s); m/z: ES− [M+H]+ 291.

(R)-1-(5-fluoro-1H-indol-3-yl)propan-2-amine

To a solution of tert-butyl(R)-(1-(5-fluoro-1H-indol-3-yl)propan-2-yl)carbamate (5.5 g, 18.81 mmol)in DCM (40 ml) was added trifluoroacetic acid (1.45 mL, 18.81 mmol) andthe mixture was stirred at room temperature for 16 hours. The reactionwas concentrated in vacuo, re-dissolved in methanol and applied to apre-wetted (methanol) SCX-2 cartridge. The cartridge was washed withmethanol (250 mL), the product eluted with 1M NH₃ in methanol solution(250 mL) and concentrated in vacuo to afford(R)-1-(5-fluoro-1H-indol-3-yl)propan-2-amine (3.56 g, 98%) as a yellowsolid. ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.16 (3H, d), 2.62 (1H, dd), 2.82(1H, dd), 3.27 (1H, ddt), 6.9-7.01 (1H, m), 7.09 (1H, s), 7.22-7.32 (2H,m), 8.16 (1H, s); m/z: ES+ [M−H]− 191.

(R)-3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoro-N-(1-(5-fluoro-1H-indol-3-yl)propan-2-yl)propan-1-amine

3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyltrifluoromethanesulfonate (1.44 g, 2.99 mmol) was added to a solution of(R)-1-(5-fluoro-1H-indol-3-yl)propan-2-amine (0.500 g, 2.6 mmol) andDIPEA (0.674 ml, 3.90 mmol) in 1,4-dioxane (9.73 ml). The reaction washeated to 80° C. for 6 hours. After cooling, the volatiles wereevaporated. The residue was dissolved in DCM (25 mL) and washed withsaturated aqueous sodium chloride (25 mL). The organic phase was driedover Na₂SO₄ and evaporated. The crude product was purified by flashsilica chromatography, elution gradient 0 to 100% EtOAc in heptane. Purefractions were evaporated to dryness to afford(R)-3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoro-N-(1-(5-fluoro-1H-indol-3-yl)propan-2-yl)propan-1-amine(1.13 g, 83%) as a colourless gum. ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.04(9H, s), 1.11 (3H, d), 2.68-2.77 (1H, m), 2.81 (1H, dd), 3.02-3.26 (3H,m), 3.74-3.88 (2H, m), 6.93 (1H, td), 7.03 (1H, d), 7.18-7.25 (2H, m),7.38 (4H, ddd), 7.4-7.49 (2H, m), 7.65 (4H, dq), 7.85 (1H, s); m/z: ES+[M+H]+ 525.

(1R,3R)-1-(3-bromo-2,6-difluorophenyl)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

(R)-3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoro-N-(1-(5-fluoro-1H-indol-3-yl)propan-2-yl)propan-1-amine(352 mg, 0.67 mmol) and 3-bromo-2,6-difluorobenzaldehyde (155 mg, 0.70mmol) were heated in toluene (3.02 mL)/acetic acid (0.33 mL) to 80° C.for 4 hours. After cooling, the volatiles were evaporated. The residuewas dissolved in DCM (25 mL) and washed with saturated NaHCO₃ solution(25 mL), then dried over Na₂SO₄ and evaporated. The crude product waspurified by flash silica chromatography, elution gradient 0 to 25% EtOAcin heptane. Pure fractions were evaporated to dryness to afford(1R,3R)-1-(3-bromo-2,6-difluorophenyl)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(483 mg, 99%) as a colourless solid. ¹H NMR (500 MHz, CDCl₃, 27° C.)1.05 (9H, s), 1.16 (3H, d), 2.54 (1H, dd), 2.76 (1H, td), 2.89-2.98 (1H,m), 3.29 (1H, ddd), 3.56-3.69 (2H, m), 3.95 (1H, ddd), 5.35 (1H, s),6.70 (1H, td), 6.88 (1H, td), 7.11-7.18 (2H, m), 7.34-7.47 (8H, m),7.6-7.67 (4H, m); m/z: ES+ [M+H]+ 727.

tert-butyl(2-(3-((1R,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-2,4-difluorophenoxy)ethyl)(3-fluoropropyl)carbamate

Tert-butyl (3-fluoropropyl)(2-hydroxyethyl)carbamate (137 mg, 0.62 mmol)was added in toluene (2.06 mL) to a flask containing(1R,3R)-1-(3-bromo-2,6-difluorophenyl)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(300 mg, 0.41 mmol), cesium carbonate (268 mg, 0.82 mmol) and Rockphos3^(rd) generation precatalyst (18.65 mg, 0.02 mmol). The reaction wasdegassed then heated to 90° C. for 2 hours. After cooling, the reactionwas diluted with EtOAc (25 mL) and washed with saturated aqueous sodiumchloride (25 mL). The organic phase was dried over Na₂SO₄ andevaporated. The crude product was purified by flash silicachromatography, elution gradient 0 to 50% EtOAc in heptane. Purefractions were evaporated to dryness to afford tert-butyl(2-(3-((1R,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-2,4-difluorophenoxy)ethyl)(3-fluoropropyl)carbamateas a beige solid. ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.04 (9H, s), 1.15(3H, d), 1.43 (9H, s), 1.91 (2H, d), 2.53 (1H, dd), 2.79 (1H, q), 2.92-3(1H, m), 3.21-3.35 (1H, m), 3.35-3.4 (1H, m), 3.41-3.54 (2H, m),3.53-3.63 (2H, m), 3.63-3.74 (1H, m), 3.89-4.01 (1H, m), 4.03 (1H, s),4.09 (1H, d), 4.37 (1H, d), 4.46 (1H, s), 5.31 (1H, s), 6.63 (1H, s),6.76-6.89 (2H, m), 7.06-7.12 (1H, m), 7.14 (1H, dd), 7.33-7.47 (6H, m),7.60 (3H, ddd), 7.63-7.68 (2H, m).

Example 55(S)-3-((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid

Tert-butyl (3-fluoropropyl)(2-hydroxyethyl)carbamate (235 mg, 1.06 mmol)was added in anhydrous toluene (4.25 mL) to a flask containing methyl(S)-3-((1R,3R)-1-(3-bromo-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(402 mg, 0.85 mmol), cesium carbonate (553 mg, 1.70 mmol) and Rockphos3^(rd) generation precatalyst (38.5 mg, 0.04 mmol). The reaction wasdegassed, then heated to 90° C. for 4 hours. A further portion oftert-butyl (3-fluoropropyl)(2-hydroxyethyl)carbamate (235 mg, 1.06 mmol)and Rockphos 3^(rd) generation precatalyst (38.5 mg, 0.04 mmol) wereadded and the reaction was heated to 90° C. overnight. The residue wasdissolved in THF (3 mL)/MeOH (3 mL) and then 2N NaOH solution (1.5 mL)was added. The reaction was stirred for 3 hours, then diluted with EtOAc(20 mL) and water (20 mL). The pH was adjusted to ˜6 by addition of 2NHCl solution and the layers were separated. The aqueous layer wasextracted with EtOAc (20 mL), then the combined organics wereevaporated. The residue was dissolved in formic acid (2 mL) and stirredat 40° C. for 1 hour. The volatiles were evaporated, then the residuewas partitioned between DCM (20 mL) and water (20 mL). The desiredproduct was observed solely in the aqueous phase. The aqueous phase wasevaporated, then the crude product was purified by preparative HPLC(Waters SunFire column, 5μ silica, 19 mm diameter, 100 mm length), usingdecreasingly polar mixtures of water (containing 0.1% NH₃) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford(S)-3-((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid (83 mg, 20%) as a pale yellow solid. ¹H NMR (500 MHz, CDCl₃, 27°C.) 0.86 (3H, d), 1.20 (3H, d), 1.82-1.97 (5H, m), 2.68-2.80 (3H, m),2.83 (3H, t), 2.94-3.07 (2H, m), 3.21 (1H, dd), 3.42 (2H, s), 3.54-3.65(1H, m), 4.02 (1H, q), 4.40 (1H, t), 4.50 (1H, t), 5.47 (1H, s), 6.18(1H, s), 6.77 (1H, dd), 6.89 (1H, t), 7.09 (2H, td), 7.14-7.22 (1H, m),7.48-7.52 (1H, m), 7.82 (1H, s). m/z: ES+ [M+H]⁺ 500.

The methyl(S)-3-((1R,3R)-1-(3-bromo-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoateused as starting material was prepared as follows:

Methyl (S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)propanoate

Trifluoromethanesulfonic anhydride (3.53 mL, 21.00 mmol), followed by2,6-dimethylpyridine (2.56 mL, 22.00 mmol) were added to a solution ofmethyl (S)-3-hydroxy-2-methylpropanoate (2.36 g, 20.0 mmol) in DCM (74mL) at 5° C. The reaction was stirred for 1 hour, then was washed with2N HCl solution (50 mL). The organic phase was washed with saturatedaqueous sodium chloride (50 mL), then dried over Na₂SO₄ and evaporatedto afford methyl(S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)propanoate (5.46g, >100%) as a red oil which was used directly. ¹H NMR (500 MHz, CDCl₃,27° C.) 1.31 (3H, d), 2.96 (1H, pd), 3.75 (3H, s), 4.56 (1H, dd), 4.69(1H, dd).

Methyl(S)-3-(((R)-1-(1H-indol-3-yl)propan-2-yl)amino)-2-methylpropanoate

Methyl (S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)propanoate (4.60g, 18.40 mmol) was added to a solution of(R)-1-(1H-indol-3-yl)propan-2-amine (2.79 g, 16 mmol) and DIPEA (3.59mL, 20.80 mmol) in 1,4-dioxane (42.1 mL) and the reaction was stirred atroom temperature for 1 hour. The reaction mixture was diluted with EtOAc(100 mL) and washed with water (100 mL). The aqueous was extracted withEtOAc (50 mL), then the combined organics were dried over Na₂SO₄ andevaporated. The crude product was purified by flash silicachromatography, elution gradient 0 to 100% EtOAc in heptane. Purefractions were evaporated to dryness to afford methyl(S)-3-(((R)-1-(1H-indol-3-yl)propan-2-yl)amino)-2-methylpropanoate (3.71g, 85%) as a pale yellow gum. ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.11 (3H,d), 1.21-1.25 (3H, m), 2.72 (1H, ddd), 2.79 (1H, dd), 2.86 (1H, dd),2.93 (2H, d), 3.13 (1H, q), 3.50 (3H, s), 7.08-7.15 (2H, m), 7.20 (1H,ddd), 7.38 (1H, dt), 7.49-7.69 (1H, m), 8.23 (1H, s). m/z: ES+ [M+H]+275.

3-Bromo-6-fluoro-2-methylbenzaldehyde

N-bromo succinimide (2.99 g, 16.80 mmol) was added to2-fluoro-6-methylbenzaldehyde (2.21 g, 16.0 mmol) in H₂SO₄ (16.00 mL)and the reaction was stirred at room temperature for 30 min. The mixturewas poured onto ice-water (150 mL). The precipitate was collected byfiltration and dried to afford 3-bromo-6-fluoro-2-methylbenzaldehyde(3.14 g, 90%) as a beige, low-melting solid. ¹H NMR (500 MHz, CDCl₃, 27°C.) 2.70 (3H, s), 6.94 (1H, ddd), 7.74 (1H, dd), 10.46 (1H, s).

Methyl(S)-3-((1R,3R)-1-(3-bromo-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate

Methyl(S)-3-(((R)-1-(1H-indol-3-yl)propan-2-yl)amino)-2-methylpropanoate (549mg, 2.0 mmol) and 3-bromo-6-fluoro-2-methylbenzaldehyde (456 mg, 2.10mmol) were heated in toluene (9.0 mL)/acetic acid (1.0 mL) to 80° C.overnight. After cooling, the volatiles were evaporated. The crudeproduct was purified by ion exchange chromatography, using an SCXcolumn. The desired product was eluted from the column using MeOH, then1M NH₃/MeOH to elute the product. The basic filtrate was evaporated,then the crude product was purified by flash silica chromatography,elution gradient 0 to 30% EtOAc in heptane. Pure fractions wereevaporated to dryness to afford methyl(S)-3-((1R,3R)-1-(3-bromo-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(421 mg, 44%) as a beige solid. ¹H NMR (500 MHz, CDCl₃, 27° C.)0.85-0.89 (3H, m), 1.11 (3H, d), 2.10 (3H, s), 2.18 (1H, p), 2.36 (1H,ddd), 2.67-2.72 (1H, m), 2.95 (1H, dd), 3.10 (1H, ddd), 3.52-3.59 (1H,m), 3.64 (3H, s), 5.39 (1H, s), 6.89 (1H, t), 7.07-7.14 (2H, m),7.19-7.22 (1H, m), 7.22 (1H, s), 7.47-7.51 (1H, m), 7.54 (1H, dd). m/z:ES− [M−H]− 471.

Example 57(S)-3-((1R,3R)-6-fluoro-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid

2N NaOH solution (1.19 mL, 2.37 mmol) was added to a solution of methyl(S)-3-((1R,3R)-1-(3-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(0.300 g, 0.47 mmol) in THF (2.37 mL)/MeOH (1.19 mL) and the reactionwas stirred at room temperature for 4 hours. The reaction was dilutedwith EtOAc (20 mL) and water (20 mL), then the pH was adjusted to ˜6 byaddition of 2N HCl solution. The layers were separated and the aqueouswas extracted with EtOAc (10 mL). The combined organics were dried overNa₂SO₄ and evaporated. The residue was dissolved in formic acid (2 mL)and warmed to 40° C. for 1 hour. The volatiles were evaporated, then thecrude product was purified by preparative HPLC (Waters SunFire column,5μ silica, 19 mm diameter, 100 mm length), using decreasingly polarmixtures of water (containing 1% NH₃) and MeCN as eluents. Fractionscontaining the desired compound were evaporated to dryness to afford(S)-3-((1R,3R)-6-fluoro-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid (0.147 g, 60%) as a beige solid. ¹H NMR (500 MHz, CDCl₃, 27° C.)0.84 (3H, d), 1.17 (3H, d), 1.83-1.89 (4H, m), 1.92 (2H, dd), 2.65 (2H,dd), 2.80 (1H, dd), 2.86 (2H, t), 3-3.1 (2H, m), 3.1-3.2 (1H, m),3.55-3.65 (1H, m), 4.03 (2H, dq), 4.38 (1H, t), 4.48 (1H, t), 5.42 (1H,s), 6.73 (1H, dd), 6.78-6.83 (1H, m), 6.83-6.89 (1H, m), 7.07 (1H, dd),7.11 (1H, dd), 7.54 (1H, s), 8.00 (1H, s). 1 exchangeable not observed.m/z: ES+ [M+H]+ 518.

The methyl(S)-3-((1R,3R)-1-(3-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoateused as starting material was prepared as follows:

Methyl(S)-3-(((R)-1-(5-fluoro-1H-indol-3-yl)propan-2-yl)amino)-2-methylpropanoate

To a cooled solution of (R)-1-(5-fluoro-1H-indol-3-yl)propan-2-amine(1.105 g, 5.75 mmol) and DIPEA (0.993 mL, 5.75 mmol) in dioxane (15 mL)at 0° C. was added methyl(S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)propanoate (1.44 g, 5.75mmol). The reaction was allowed to warm to room temperature and stirredovernight. The reaction was diluted with EtOAc (50 mL) and washed withwater (50 mL). The organic phase was dried over Na₂SO₄ and evaporated.The crude product was purified by flash silica chromatography, elutiongradient 25 to 100% EtOAc in heptane. Pure fractions were evaporated todryness to afford methyl(S)-3-(((R)-1-(5-fluoro-1H-indol-3-yl)propan-2-yl)amino)-2-methylpropanoate(1.520 g, 90%) as a pale yellow oil. ¹H NMR (500 MHz, CDCl₃, 27° C.)1.13 (3H, d), 1.26-1.29 (3H, m), 2.67-2.85 (2H, m), 2.86-2.98 (3H, m),3.14 (1H, h), 3.53 (3H, s), 6.95 (1H, td), 7.17-7.23 (2H, m), 7.30 (1H,dd), 8.37 (1H, s). m/z: ES+ [M+H]+ 293.

Methyl(S)-3-((1R,3R)-1-(3-bromo-6-fluoro-2-methylphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate

Methyl(S)-3-(((R)-1-(5-fluoro-1H-indol-3-yl)propan-2-yl)amino)-2-methylpropanoate(439 mg, 1.5 mmol) and 3-bromo-6-fluoro-2-methylbenzaldehyde (326 mg,1.50 mmol) were heated in toluene (6.75 mL)/acetic acid (0.75 mL) to110° C. overnight. The volatiles were evaporated, then the residue wasdissolved in DCM (25 mL) and washed with saturated NaHCO₃ solution (25mL). The organic was dried over Na₂SO₄ and evaporated. The crude productwas purified by flash silica chromatography, elution gradient 0 to 30%EtOAc in heptane. Pure fractions were evaporated to dryness to affordmethyl(S)-3-((1R,3R)-1-(3-bromo-6-fluoro-2-methylphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(204 mg, 28%) as a pale yellow solid. ¹H NMR (500 MHz, CDCl₃, 27° C.)0.87 (3H, d), 1.11 (3H, d), 2.10 (3H, s), 2.16 (1H, q), 2.35 (1H, ddd),2.63 (1H, d), 2.95 (1H, dd), 3.07 (1H, ddd), 3.52-3.59 (1H, m), 3.64(3H, s), 5.37 (1H, s), 6.84 (1H, td), 6.90 (1H, t), 7.08-7.15 (2H, m),7.20 (1H, s), 7.55 (1H, dd). m/z: ES+ [M+H]+ 491.

Methyl(S)-3-((1R,3R)-1-(3-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate

Tert-butyl (3-fluoropropyl)(2-hydroxyethyl)carbamate (342 mg, 1.55 mmol)was added in toluene (6.18 mL) to a flask containing methyl(S)-3-((1R,3R)-1-(3-bromo-6-fluoro-2-methylphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(380 mg, 0.77 mmol), cesium carbonate (628 mg, 1.93 mmol) and Rockphos3^(rd) generation precatalyst (70.0 mg, 0.08 mmol). The reaction wasdegassed, then heated to 105° C. for 3 hours. The reaction was dilutedwith DCM (25 mL) and washed with saturated aqueous sodium chloride (25mL). The organic layer was dried over Na₂SO₄ and evaporated, then thecrude product was purified by flash silica chromatography, elutiongradient 0 to 60% EtOAc in heptane. Pure fractions were evaporated todryness to afford methyl(S)-3-((1R,3R)-1-(3-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(321 mg, 66%) as a beige solid. m/z: ES+ [M+H]+ 632.

Example 117(R)-3-((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid

(R)-3-((1R,3R)-1-(3-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid (200 mg, 0.33 mmol) was stirred in formic acid (2.0 mL) at 40° C.for 1 hour. The volatiles were evaporated, then the crude product waspurified by preparative HPLC (Waters XSelect CSH C18 column, 5μ silica,19 mm diameter, 100 mm length), using decreasingly polar mixtures ofwater (containing 1% NH₃) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness to afford(R)-3-((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid (120 mg, 72%) as a colourless solid. ¹H NMR (500 MHz, CDCl₃, 27°C.) 1.10 (3H, d), 1.22 (3H, d), 1.80 (3H, s), 1.88 (2H, dq), 2.56 (1H,t), 2.71-2.90 (5H, m), 2.95 (1H, s), 2.99-3.07 (1H, m), 3.22-3.32 (1H,m), 3.85 (1H, p), 4.06 (2H, t), 4.45 (1H, t), 4.55 (1H, t), 5.35 (1H,s), 6.84 (1H, dd), 6.93 (1H, d), 7.08-7.17 (2H, m), 7.19-7.23 (1H, m),7.38 (1H, s), 7.51 (1H, dd). (2×exchangeables not observed.); m/z: ES+[M+H]+ 500.

The(R)-3-((1R,3R)-1-(3-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid used as starting material was prepared as follows:

Methyl (R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)propanoate

Trifluoromethanesulfonic anhydride (7.48 mL, 44.44 mmol) was added to asolution of methyl (R)-3-hydroxy-2-methylpropanoate (5.00 g, 42.3 mmol)in DCM (128 mL) at 5° C., followed by addition of 2,6-dimethylpyridine(5.42 mL, 46.6 mmol). The reaction was stirred for 1 hour, then waswashed with 2N HCl solution (100 mL), dried over MgSO₄ and evaporated toafford methyl (R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)propanoate(11.64 g, >100%) as a red oil which was used without furtherpurification. ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.31 (3H, d), 2.91-3.03(1H, m), 3.75 (3H, s), 4.56 (1H, dd), 4.69 (1H, dd).

Methyl(R)-3-(((R)-1-(1H-indol-3-yl)propan-2-yl)amino)-2-methylpropanoate

Methyl (R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)propanoate (10.46g, 41.80 mmol) was added in DCM (20 mL) to a solution of(R)-1-(1H-indol-3-yl)propan-2-amine (6.62 g, 38.0 mmol) and DIPEA (8.21mL, 47.5 mmol) in DCM (107 mL) at 5° C. The reaction was warmed to roomtemperature and stirred overnight. The reaction was washed withsaturated aqueous sodium chloride (50 mL), then dried over Na₂SO₄ andevaporated. The crude product was purified by flash silicachromatography, elution gradient 25 to 100% EtOAc in heptane. Purefractions were evaporated to dryness to afford methyl(R)-3-(((R)-1-(1H-indol-3-yl)propan-2-yl)amino)-2-methylpropanoate (8.45g, 81%) as an orange liquid. ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.10 (3H,d), 1.12 (3H, d), 2.53-2.71 (2H, m), 2.74-2.89 (2H, m), 2.94 (1H, dd),3.05 (1H, h), 3.48 (3H, s), 7.04 (1H, d), 7.11 (1H, ddd), 7.18 (1H,ddd), 7.35 (1H, dt), 7.53-7.64 (1H, m), 8.12 (1H, s). (1×exchangeablenot observed); m/z: ES+ [M+H]+ 275.

Methyl(R)-3-((1R,3R)-1-(3-bromo-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate

Methyl(R)-3-(((R)-1-(1H-indol-3-yl)propan-2-yl)amino)-2-methylpropanoate (686mg, 2.50 mmol) and 3-bromo-6-fluoro-2-methylbenzaldehyde (570 mg, 2.63mmol) were heated in toluene (9.0 mL)/acetic acid (1.0 mL) to 90° C. for6 hours. After cooling, the reaction mixture was evaporated. The residuewas dissolved in DCM (25 mL) and washed with saturated aqueous NaHCO₃(25 mL). The aqueous was extracted with DCM (25 mL), then the combinedorganics were dried over Na₂SO₄ and evaporated. The crude product waspurified by flash silica chromatography, elution gradient 0 to 30% EtOAcin heptane. Product containing fractions were evaporated to dryness toafford methyl(R)-3-((1R,3R)-1-(3-bromo-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(795 mg, 67%) as a beige solid. ¹H NMR (500 MHz, CDCl₃, 27° C.)1.01-1.05 (3H, m), 1.09 (3H, d), 2.03 (3H, s), 2.57-2.64 (3H, m),2.69-2.75 (1H, m), 3.08-3.14 (1H, m), 3.52 (3H, s), 3.66-3.74 (1H, m),5.31 (1H, s), 6.90 (1H, t), 7.05-7.14 (2H, m), 7.18-7.22 (2H, m), 7.49(1H, dd), 7.54 (1H, dd); m/z: ES+ [M+H]+ 473.

Methyl(R)-3-((1R,3R)-1-(3-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate

Tert-butyl (3-fluoropropyl)(2-hydroxyethyl)carbamate (351 mg, 1.58 mmol)was added in toluene (5.0 mL) to a flask containing methyl(R)-3-((1R,3R)-1-(3-bromo-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(500 mg, 1.06 mmol), cesium carbonate (858 mg, 2.64 mmol) and rockphos3^(rd) generation precatalyst (45.1 mg, 0.05 mmol) under nitrogen. Thereaction was degassed, then heated to 90° C. for 4 hours. After cooling,the reaction was diluted with DCM (25 mL) and washed with saturatedaqueous sodium chloride (25 mL). The aqueous layer was extracted withDCM (25 mL), then the combined organics were dried over Na₂SO₄ andevaporated. The crude product was purified by flash silicachromatography, elution gradient 0 to 40% EtOAc in heptane. Productcontaining fractions were evaporated to dryness to afford methyl(R)-3-((1R,3R)-1-(3-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(425 mg, 66%) as a beige solid. ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.03(3H, d), 1.09 (3H, d), 1.43 (9H, s), 1.82 (3H, s), 1.85-1.97 (2H, m),2.53-2.61 (1H, m), 2.61-2.68 (1H, m), 2.70 (1H, d), 3.12 (1H, ddd), 3.39(2H, t), 3.49 (3H, s), 3.52-3.59 (3H, m), 3.64-3.73 (1H, m), 4.01 (2H,d), 4.36 (1H, s), 4.45 (1H, s), 5.27 (1H, s), 6.79 (1H, dd), 6.91 (1H,t), 7.01-7.12 (2H, m), 7.16-7.21 (1H, m), 7.23-7.26 (1H, m), 7.47-7.52(1H, m). m/z: ES+ [M+H]+ 614.

(R)-3-((1R,3R)-1-(3-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid

2N NaOH solution (2.00 mL, 4.00 mmol) was added to a solution of methyl(R)-3-((1R,3R)-1-(3-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(400 mg, 0.65 mmol) in THF (2.5 mL)/MeOH (2.5 mL) and the reaction wasstirred at room temperature for 2 hours. The reaction was diluted withEtOAc (25 mL) and water (25 mL) then the pH was adjusted to ˜5 byaddition of 2N HCl solution. The layers were separated and the aqueouslayer was extracted with EtOAc (25 mL). The combined organics were driedover Na₂SO₄ and evaporated. The crude product was purified bypreparative HPLC (Waters XSelect CSH C18 column, 5μ silica, 30 mmdiameter, 100 mm length), using decreasingly polar mixtures of water(containing 1% NH₃) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness to afford(R)-3-((1R,3R)-1-(3-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid (225 mg, 58%) as a colourless solid. ¹H NMR (500 MHz, CDCl₃, 27°C.) 1.13 (3H, d), 1.24 (3H, d), 1.41-1.47 (9H, m), 1.76 (3H, s), 1.88(2H, d), 2.57 (1H, t), 2.75 (1H, s), 2.87 (2H, d), 3.29 (1H, d), 3.39(2H, s), 3.58 (2H, s), 3.82-3.96 (1H, m), 4.10 (2H, d), 4.38 (1H, s),4.47 (1H, s), 5.39 (1H, s), 6.84 (1H, s), 6.95 (1H, s), 7.08-7.19 (2H,m), 7.23 (1H, d), 7.40 (1H, d), 7.50-7.57 (1H, m). (1×exchangeable notobserved.); m/z: ES+ [M+H]+ 600.

Example 121(R)-3-((1R,3R)-6-fluoro-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid

Aqueous sodium hydroxide (2N, 0.45 mL, 0.90 mmol) was added to asolution of methyl(R)-3-((1R,3R)-1-(3-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(0.11 g, 0.18 mmol) in THF (0.54 mL) and MeOH (0.27 mL) and the reactionwas stirred at room temperature for 21 hours. The reaction was thendiluted with water, acidified to pH 6 by addition of aqueous HCl (2N),and extracted with ethyl acetate (2×). The combined organic layers weredried over Na₂SO₄, filtered and concentrated under reduced pressure toafford(R)-3-((1R,3R)-1-(3-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid (0.095 g, 85%) as an orange gum. This gum was dissolved in formicacid (1 mL) and stirred at room temperature for 3 hours. The reactionwas then concentrated under reduced pressure, and the resulting residuewas purified by preparative SFC (Chiralpak IC, 5 μm, 21.2 mm diameter,250 mm length, 75 mL/min flow rate), eluting with isocratic (25% MeOHcontaining 0.2% NH₄OH) in CO₂, to afford(R)-3-((1R,3R)-6-fluoro-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid (0.034 g, 42%) as a colorless solid. ¹H NMR (300 MHz, DMSO-d₆, 27°C.) 0.88 (3H, d), 0.99 (3H, d), 1.63-1.95 (6H, m), 2.52-2.65 (4H, m),2.77-2.85 (2H, m), 2.95 (1H, br dd), 3.84-4.00 (2H, m), 4.44 (2H, dt),5.17 (1H, s), 6.77 (1H, td), 6.87-6.93 (1H, m), 6.93-7.01 (1H, m),7.08-7.15 (2H, m), 10.29 (1H, s). Two hydrogen multiplet obscured bywater; another two hydrogens not observed. m/z: ES+ [M+H]+ 518. Alsoisolated was(R)-3-((1S,3R)-6-fluoro-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid (0.015 g, 19%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.)0.88 (3H, d), 0.99 (3H, d), 1.63-1.95 (6H, m), 2.52-2.65 (4H, m),2.77-2.85 (2H, m), 2.95 (1H, br dd), 3.84-4.00 (2H, m), 4.44 (2H, dt),5.17 (1H, s), 6.77 (1H, td), 6.87-6.93 (1H, m), 6.93-7.01 (1H, m),7.08-7.15 (2H, m), 10.29 (1H, s). Two hydrogen multiplet obscured bywater; another two hydrogens not observed. m/z: ES+ [M+H]+ 518.

Procedures used to prepare the starting material methyl(R)-3-((1R,3R)-1-(3-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoateare described below.

Methyl(R)-3-(((R)-1-(5-fluoro-1H-indol-3-yl)propan-2-yl)amino)-2-methylpropanoate

A solution of crude methyl(R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)propanoate (0.456 g, 1.82mmol) in DCM (1 mL) was added to a solution of(R)-1-(5-fluoro-1H-indol-3-yl)propan-2-amine (0.35 g, 1.8 mmol) andDIPEA (0.32 mL, 1.8 mmol) in 1,4-dioxane (7.0 mL) at 0° C. The reactionwas allowed to warm to room temperature and stirred under theseconditions for 18 hours. The reaction was diluted with ethyl acetate andwashed with water. The organic layer was dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The resulting residue waspurified by flash silica chromatography, elution gradient 25 to 100%EtOAc in hexane. Product fractions were concentrated under reducedpressure to afford methyl(R)-3-(((R)-1-(5-fluoro-1H-indol-3-yl)propan-2-yl)amino)-2-methylpropanoate(0.33 g, 62%) as a pale yellow oil. ¹H NMR (300 MHz, DMSO-d₆, 27° C.)0.96 (3H, d), 1.05 (3H, d), 2.53-3.03 (6H, m), 3.52 (3H, s), 6.88 (1H,td), 7.21 (1H, d), 7.24 (1H, dd), 7.31 (1H, dd), 10.92 (1H, br s). m/z:ES+ [M+H]+ 292.

Methyl(R)-3-((1R,3R)-1-(3-bromo-6-fluoro-2-methylphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate

A solution of methyl(R)-3-(((R)-1-(5-fluoro-1H-indol-3-yl)propan-2-yl)amino)-2-methylpropanoate(0.332 g, 1.14 mmol) and 3-bromo-6-fluoro-2-methylbenzaldehyde (0.259 g,1.19 mmol) in toluene (6.5 mL) and acetic acid (0.72 mL) was heated at80° C. for 24 hours. The reaction temperature was increased to 90° C.,and the reaction was maintained under these conditions for 24 hours. Thereaction temperature was then increased to 100° C., and the reaction wasmaintained under these conditions for 24 hours. The reaction was thencooled, concentrated under reduced pressure, and the resulting residuewas dissolved in DCM and washed with saturated aqueous NaHCO₃. Theorganic layer was dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The resulting residue was purified by flash silicachromatography, elution gradient 0 to 30% EtOAc in hexane. Productfractions were concentrated under reduced pressure to afford methyl(R)-3-((1R,3R)-1-(3-bromo-6-fluoro-2-methylphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(0.170 g, 30%) as a pale yellow solid. m/z: ES+ [M+H]+ 491.

Methyl(R)-3-((1R,3R)-1-(3-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate

A solution of tert-butyl (3-fluoropropyl)(2-hydroxyethyl)carbamate (0.15g, 0.69 mmol) in toluene (2.77 mL) was added to a flask containingmethyl(R)-3-((1R,3R)-1-(3-bromo-6-fluoro-2-methylphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(0.17 g, 0.35 mmol), cesium carbonate (0.28 g, 0.87 mmol) and RockPhos3^(rd) Generation Precatalyst (0.03 g, 0.03 mmol). The resulting mixturewas degassed and then heated at 100° C. for 3 hours. Additional RockPhos3^(rd) Generation Precatalyst (64 mg) was added, and the reaction wasmaintained under these conditions for another hour. The reaction wasthen allowed to cool to room temperature, diluted with DCM and washedwith saturated to aqueous sodium chloride. The organic layer was driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresulting residue was purified by flash silica chromatography, elutiongradient 0 to 60% EtOAc in hexane. Product fractions were concentratedunder reduced pressure to afford methyl(R)-3-((1R,3R)-1-(3-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2methylpropanoate (0.11 g, 52%) as a beige solid. m/z: ES+ [M+H]+ 632.

Example 124(S)-3-((1R,3R)-1-(3-(2-((3,3-Difluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-3-methyl-,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid

2M Sodium hydroxide (0.020 mL, 0.04 mmol) was added to a solution ofmethyl(S)-3-((1R,3R)-1-(3-(2-((3,3-difluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(0.007 g, 0.01 mmol) in methanol (0.2 mL). The reaction mixture wasstirred at room temperature overnight and then evaporated. The crudeproduct was purified by preparative HPLC (Waters CSH C18 OBD column, 5μsilica, 30 mm diameter, 100 mm length), using decreasingly polarmixtures of water (containing 1% NH₃) and MeCN as eluents to afford(S)-3-((1R,3R)-1-(3-(2-((3,3-difluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid (3.0 mg, 44%) as a dry film. ¹H NMR (500 MHz, CDCl₃, 27° C.) 0.91(3H, d), 1.26 (3H, d), 1.53-2.07 (6H, m), 2.71-2.87 (4H, m), 2.89-3.04(3H, m), 3.29 (1H, d), 3.57-3.67 (1H, m), 3.95-4.05 (2H, m), 5.54 (1H,s), 5.91 (1H, tt), 6.83 (1H, dd), 6.96 (1H, t), 7.10-7.17 (2H, m),7.21-7.24 (1H, m), 7.40 (1H, s), 7.49-7.54 (1H, m). (2 exchangeables notseen). m/z: ES+ [M+H]+ 518.

The methyl(S)-3-((1R,3R)-1-(3-(2-((3,3-difluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoateused as starting material was prepared as follows:

Methyl(S)-3-((1R,3R)-1-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate

RockPhos 3^(rd) generation precatalyst (0.018 g, 0.02 mmol) was added toa degassed suspension of methyl(S)-3-((1R,3R)-1-(3-bromo-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(0.200 g, 0.42 mmol), 2-((tert-butyldimethylsilyl)oxy)ethan-1-ol (0.089g, 0.51 mmol) and cesium carbonate (0.344 g, 1.06 mmol) in toluene (3mL). The reaction was heated to 90° C. overnight and the reactionmixture was allowed to cool. The reaction mixture was diluted with water(20 mL) and DCM (50 mL). The organic phase was separated and evaporated.The crude product was purified by flash silica chromatography, elutiongradient 0 to 100% EtOAc in heptane to give impure methyl(S)-3-((1R,3R)-1-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(0.038 g, 17%). m/z: ES+ [M+H]+ 569.

Methyl(S)-3-((1R,3R)-1-(6-fluoro-2-methyl-3-(2-((methylsulfonyl)oxy)ethoxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate

To a solution of methyl(S)-3-((1R,3R)-1-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(0.038 g, 0.07 mmol) in tetrahydrofuran (1 mL) was addedtetrabutylammonium fluoride (1.0 M in THF, 0.134 mL, 0.13 mmol). Thereaction mixture was stirred at room temperature for 2 hours and thenevaporated to a gum which was dissolved in dichloromethane (2 mL) and towhich DIPEA (0.035 mL, 0.20 mmol) was added. Methanesulfonyl chloride(8.0 μl, 0.10 mmol) was added to this solution and the reaction mixturewas stirred at room temperature for 1 hour. The reaction mixture wasdiluted with DCM (5 mL), washed with water and the organic phaseevaporated to give methyl(S)-3-((1R,3R)-1-(6-fluoro-2-methyl-3-(2-((methylsulfonyl)oxy)ethoxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(0.028 g, 0.05 mmol). m/z: ES+ [M+H]+ 569.

Methyl(S)-3-((1R,3R)-1-(3-(2-((3,3-difluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate

3,3-Difluoro-1-aminopropane hydrochloride (8 mg, 0.06 mmol), methyl(S)-3-((1R,3R)-1-(6-fluoro-2-methyl-3-(2-((methylsulfonyl)oxy)ethoxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(0.028 g, 0.05 mmol), potassium carbonate (0.036 g, 0.26 mmol) andsodium iodide (0.016 g, 0.11 mmol) in acetonitrile (0.5 mL) were heatedto 85° C. under microwave irradiation for 4 hours. The reaction mixturewas partitioned between water (5 mL) and DCM (5 mL) and the organicphase was evaporated. The crude product was purified by flash silicachromatography, elution gradient 0 to 100% EtOAc in heptane to affordmethyl(S)-3-((1R,3R)-1-(3-(2-((3,3-difluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(7.0 mg, 25%) as a solid. ¹H NMR (500 MHz, CDCl₃, 27° C.) 0.87 (3H, d),1.11 (3H, d), 1.88 (3H, s), 1.93-2.04 (2H, m), 2.21 (1H, h), 2.40 (1H,dd), 2.68 (1H, d), 2.82 (2H, t), 2.91-3.03 (3H, m), 3.10 (1H, ddd),3.50-3.58 (1H, m), 3.63 (3H, s), 3.90-4.00 (2H, m), 5.34 (1H, s), 5.90(1H, tt), 6.80 (1H, dd), 6.91 (1H, t), 7.03-7.13 (2H, m), 7.15-7.22 (1H,m), 7.42-7.54 (1H, m). (2 exchangables not seen). m/z: ES+ [M+H]+ 532.

Example 126(S)-3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid

Tert-butyl (3-fluoropropyl)(2-hydroxyethyl)carbamate (212 mg, 0.96 mmol)was added in toluene (3.20 mL) to a flask containing methyl(S)-3-((1R,3R)-1-(2-chloro-5-fluoro-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(275 mg, 0.64 mmol), cesium carbonate (416 mg, 1.28 mmol) and rockphos3^(rd) generation precatalyst (29.0 mg, 0.03 mmol). The reaction wasdegassed, then heated to 90° C. for 4 hours. After cooling, the reactionwas diluted with DCM (20 mL) and saturated aqueous sodium chloride (20mL). The layers were separated and the aqueous layer was extracted withDCM (20 mL). The combined organics were evaporated. The crude productwas dissolved in THF (2.5 mL) and MeOH (2.5 mL), then 2N NaOH solution(2.5 mL) was added and the reaction was stirred at room temperature fora further 2 hours. The reaction was diluted with EtOAc (20 mL) and water(20 mL) and the pH was adjusted to ˜5 by addition of 2N HCl solution.The layers were separated, then the aqueous layer was extracted withEtOAc (2×15 mL). The combined organics were dried over Na₂SO₄ andevaporated. The crude product was purified by flash silicachromatography, elution gradient 25 to 100% EtOAc in heptane. Productcontaining fractions were evaporated to dryness to afford(S)-3-((1R,3R)-1-(2-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-5-fluoro-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid (350 mg), which was impure. The residue was dissolved in formicacid (2 mL) and warmed to 40° C. for 1 hour. The volatiles wereevaporated, then the crude product was purified by preparative HPLC(Waters SunFire column, 5μ silica, 19 mm diameter, 100 mm length), usingdecreasingly polar mixtures of water (containing 1% NH₃) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford(S)-3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid (65.0 mg, 20%) as a beige solid. ¹H NMR (500 MHz, CDCl₃, 27° C.)0.96 (3H, d), 1.19 (3H, d), 1.87 (3H, s), 1.90-2.05 (3H, m), 2.68-2.79(2H, m), 2.88 (1H, dd), 3.04 (2H, t), 3.19 (1H, d), 3.24 (2H, s), 3.61(1H, d), 4.44 (2H, dt), 4.52 (1H, t), 4.57-4.69 (1H, m), 5.40 (1H, s),7.07-7.17 (2H, m), 7.21 (1H, d), 7.44-7.55 (1H, m), 7.84 (1H, s), 8.25(1H, s), 8.34 (1H, s). (1×exchangeable not observed.) m/z: ES+ [M+H]+501.

The methyl(S)-3-((1R,3R)-1-(2-chloro-5-fluoro-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoateused as starting material was prepared as follows:

2-chloro-5-fluoro-3-methylisonicotinaldehyde

LDA solution (2M, 3.85 mL, 7.70 mmol) was added to a cooled solution of2-chloro-5-fluoro-3-methylpyridine (1.02 g, 7.00 mmol) in THF (22.9 mL)at −78° C. The reaction was stirred for 30 min, then methyl formate(1.30 mL, 21.0 mmol) was added and the reaction was stirred for afurther 30 minutes. The reaction was quenched by addition of 1N HClsolution (20 mL) and extracted with EtOAc (40 mL). The organic phase waswashed with saturated aqueous sodium chloride, dried over Na₂SO₄ andevaporated. The crude product was purified by flash silicachromatography, elution gradient 0 to 20% EtOAc in heptane. Productcontaining fractions were evaporated to dryness to afford2-chloro-5-fluoro-3-methylisonicotinaldehyde (754 mg, 62%) as a strawcoloured liquid. ¹H NMR (500 MHz, CDCl₃, 27° C.) 2.65 (3H, s), 8.33 (1H,s), 10.51 (1H, s).

Methyl(S)-3-((1R,3R)-1-(2-chloro-5-fluoro-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate

Methyl(S)-3-(((R)-1-(1H-indol-3-yl)propan-2-yl)amino)-2-methylpropanoate (439mg, 1.60 mmol) and 2-chloro-5-fluoro-3-methylisonicotinaldehyde (292 mg,1.68 mmol) were heated in toluene (7.20 mL)/acetic acid (0.80 mL) to 90°C. for 5 hours. After cooling, the volatiles were evaporated. Theresidue was dissolved in DCM (20 mL) and washed with saturated aqueousNaHCO₃ (20 mL). The layers were separated, then the organic phase wasdried over Na₂SO₄ and evaporated. The crude product was purified byflash silica chromatography, elution gradient 0 to 30% EtOAc in heptane.Product containing fractions were evaporated to dryness to afford methyl(S)-3-((1R,3R)-1-(2-chloro-5-fluoro-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(283 mg, 41%) as a beige solid. ¹H NMR (500 MHz, CDCl₃, 27° C.) 0.91(3H, d), 1.11 (3H, d), 2.10 (3H, s), 2.27 (2H, ddd), 2.72 (1H, d), 3.02(1H, dd), 3.11 (1H, ddd), 3.53-3.60 (1H, m), 3.65 (3H, s), 5.37 (1H, s),7.09-7.17 (2H, m), 7.24 (1H, dd), 7.30 (1H, s), 7.51 (1H, d), 8.20 (1H,s). m/z: ES+ [M+H]+ 430.

Example 127(R)-3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid

(R)-3-((1R,3R)-1-(2-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-5-fluoro-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid (450 mg, 0.75 mmol) was stirred in formic acid (4.0 mL) at 40° C.for 1 hour. The volatiles were evaporated, then the crude product waspurified by preparative HPLC (Waters XSelect CSH C18 column, 5μ silica,19 mm diameter, 100 mm length), using decreasingly polar mixtures ofwater (containing 1% NH₃) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness to afford(R)-3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid (302 mg, 81%) as a colourless solid. ¹H NMR (500 MHz, CDCl₃, 27°C.) 1.01 (3H, d), 1.12 (3H, d), 1.85 (3H, s), 1.87-1.98 (2H, m),2.45-2.52 (1H, m), 2.57 (1H, ddd), 2.63 (1H, dd), 2.75 (1H, d), 2.81(2H, t), 2.89 (1H, ddd), 3.12 (1H, ddd), 3.17 (1H, ddd), 3.73 (1H, q),4.23 (1H, ddd), 4.40 (1H, t), 4.50 (1H, t), 4.69 (1H, ddd), 5.25 (1H,s), 7.01-7.16 (2H, m), 7.20 (1H, dd), 7.41 (1H, s), 7.50 (1H, dd), 7.86(1H, s). (2×exchangeables not observed); m/z: ES+ [M+H]+ 501.

The(R)-3-((1R,3R)-1-(2-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-5-fluoro-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid used as starting material was prepared as follows:

Methyl(R)-3-((1R,3R)-1-(2-chloro-5-fluoro-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate

Methyl(R)-3-(((R)-1-(1H-indol-3-yl)propan-2-yl)amino)-2-methylpropanoate (741mg, 2.7 mmol) and 2-chloro-5-fluoro-3-methylisonicotinaldehyde (492 mg,2.84 mmol) were heated in toluene (9.72 mL)/acetic acid (1.08 mL) to 90°C. for 6 hours. After cooling, the reaction mixture was evaporated. Theresidue was dissolved in DCM (25 mL) and washed with saturated aqueousNaHCO₃ (25 mL). The aqueous layer was extracted with DCM (25 mL), thenthe combined organics were dried over Na₂SO₄ and evaporated. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 30% EtOAc in heptane. Product containing fractions were evaporated todryness to afford methyl(R)-3-((1R,3R)-1-(2-chloro-5-fluoro-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(950 mg, 82%) as a beige solid. ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.04(3H, d), 1.09 (3H, d), 2.01 (3H, s), 2.46-2.57 (1H, m), 2.62-2.70 (2H,m), 2.75 (1H, d), 3.11 (1H, ddd), 3.53 (3H, s), 3.68-3.78 (1H, m), 5.30(1H, s), 7.08-7.18 (2H, m), 7.21-7.26 (1H, m), 7.46-7.52 (1H, m), 7.53(1H, s), 8.15 (1H, s); m/z: ES+ [M+H]+ 430.

Methyl(R)-3-((1R,3R)-1-(2-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-5-fluoro-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate

Tert-butyl (3-fluoropropyl)(2-hydroxyethyl)carbamate (581 mg, 2.63 mmol)was added to a suspension of methyl(R)-3-((1R,3R)-1-(2-chloro-5-fluoro-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(752 mg, 1.75 mmol), cesium carbonate (1.42 g, 4.38 mmol) and rockphos3^(rd) generation precatalyst (74.7 mg, 0.09 mmol) in degassed toluene(8.75 mL). The reaction was heated to 90° C. and stirred for 4 hours.After cooling, the reaction was diluted with DCM (25 mL) and washed withsaturated aqueous sodium chloride (25 mL). The aqueous layer wasextracted with DCM (25 mL), then the combined organics were dried overNa₂SO₄ and evaporated. The crude product was purified by flash silicachromatography, elution gradient 0 to 40% EtOAc in heptane. Productcontaining to fractions were evaporated to dryness to afford methyl(R)-3-((1R,3R)-1-(2-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-5-fluoro-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(571 mg, 53%) as a beige solid. ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.04(3H, d), 1.08 (3H, d), 1.42 (9H, d), 1.82 (3H, s), 1.84-2.00 (2H, m),2.50-2.60 (1H, m), 2.60-2.77 (3H, m), 3.10 (1H, ddd), 3.30-3.41 (2H, m),3.51 (3H, s), 3.53-3.61 (2H, m), 3.65-3.73 (1H, m), 4.31-4.44 (3H, m),4.46 (1H, t), 5.22 (1H, s), 7.10 (2H, dqt), 7.20 (1H, dd), 7.27-7.40(1H, m), 7.49 (1H, dd), 7.88 (1H, s); m/z: ES+ [M+H]+ 615.

(R)-3-((1R,3R)-1-(2-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-5-fluoro-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid

2N NaOH solution (2.68 mL, 5.37 mmol) was added to a solution of methyl(R)-3-((1R,3R)-1-(2-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-5-fluoro-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(550 mg, 0.89 mmol) in THF (3.1 mL)/MeOH (3.1 mL). The reaction wasstirred at room temperature for 2 hours, then was diluted with EtOAc (25mL) and water (25 mL). The pH was adjusted to ˜5 by addition of 2N HClsolution and the layers were separated. The aqueous layer was extractedwith EtOAc (25 mL), then the combined organics were dried over Na₂SO₄and evaporated. The crude product was passed through a plug of silicagel, eluting with EtOAc. The filtrate was evaporated to afford(R)-3-((1R,3R)-1-(2-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-5-fluoro-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid (492 mg, 92%) as a beige solid. m/z: ES+ [M+H]+ 601.

Example 143(S)-3-((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid

Iodomethane (6.85 μl, 0.11 mmol) was added to a solution of(S)-3-((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid (50 mg, 0.10 mmol) and DIPEA (51.9 μl, 0.30 mmol) in acetonitrile(0.95 mL). The reaction was stirred at room temperature for 3 hours. Thevolatiles were evaporated, then the crude product was purified bypreparative HPLC (Waters XSelect CSH C18 column, 5μ silica, 19 mmdiameter, 100 mm length), using decreasingly polar mixtures of water(containing 1% NH₃) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness to afford(S)-3-((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid (14.4 mg, 28%) as a colourless solid. ¹H NMR (500 MHz, CDCl₃, 27°C.) 0.90 (3H, d), 1.27 (3H, d), 1.70-1.90 (5H, m), 2.32 (3H, s), 2.57(2H, t), 2.67-2.77 (1H, m), 2.77-2.82 (4H, m), 2.96 (1H, dd), 3.29 (1H,d), 3.55-3.68 (1H, m), 4.00 (2H, t), 4.42 (1H, t), 4.51 (1H, t), 5.55(1H, s), 6.83 (1H, dd), 6.95 (1H, t), 7.13 (2H, dtd), 7.22 (1H, dd),7.46 (1H, s), 7.48-7.58 (1H, m). (1×exchangeable not observed). m/z: ES+[M+H]+ 514.

Example 145(S)-3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid

Methyl(S)-3-(((R)-1-(1H-indol-3-yl)propan-2-yl)amino)-2-methylpropanoate (151mg, 0.55 mmol) and5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylisonicotinaldehyde(300 mg, 50% wt, 0.55 mmol) were heated in toluene (2.50 mL)/acetic acid(0.278 mL) to 90° C. for 4 hours. After cooling, the volatiles wereevaporated. The residue was dissolved in DCM (20 mL) and washed withsaturated aqueous NaHCO₃ solution (20 mL). The aqueous layer wasextracted with DCM (20 mL), then the combined organics were dried overNa₂SO₄ and evaporated. The crude product was purified by flash silicachromatography, elution gradient 100% EtOAc. Fractions containing theproduct were evaporated to dryness to afford a yellow gum (300 mg). Theresidue was dissolved in THF (2 mL) and methanol (2 mL), then 2N NaOHsolution (2 mL) was added. The mixture was stirred at room temperaturefor 2 hours. The reaction was diluted with EtOAc (20 mL) and water (20mL). The pH was adjusted to ˜5 by addition of 2N HCl solution, then thelayers were separated. The aqueous layer was extracted with EtOAc (20mL), then the combined organic layers were dried over Na₂SO₄ andevaporated to dryness. The crude product was purified by preparativeHPLC (Waters XSelect CSH C18 column, 5μ silica, 19 mm diameter, 100 mmlength), using decreasingly polar mixtures of water (containing 1% NH₃)and MeCN as eluents. Fractions containing the desired compound wereevaporated to dryness to afford(S)-3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid (98 mg, 35%) as a colourless solid. ¹H NMR (500 MHz, CDCl₃, 27° C.)0.99 (3H, d), 1.23 (3H, d), 1.77-1.86 (2H, m), 1.87 (3H, d), 2.32 (3H,s), 2.59 (2H, t), 2.72-2.90 (6H, m), 3.21 (1H, d), 3.54-3.64 (1H, m),4.36 (1H, ddd), 4.40 (1H, t), 4.43-4.48 (1H, m), 4.50 (1H, t), 5.43 (1H,s), 7.14 (2H, dtd), 7.24 (1H, d), 7.52 (2H, d), 7.90 (1H, s).(1×exchangeable not observed.) m/z: ES+ [M+H]+ 515.

The5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylisonicotinaldehydeused as starting material was prepared as follows:

2-((3-fluoropropyl)(methyl)amino)ethan-1-ol

1-Fluoro-3-iodopropane (5.64 g, 30.0 mmol) was added to a suspension of2-(methylamino)ethan-1-ol (2.65 mL, 33.0 mmol) and potassium carbonate(8.28 g, 60.0 mmol) in acetonitrile (88 mL). The reaction was heated to50° C. for 2 hours, then cooled and stirred at room temperatureovernight. The volatiles were evaporated, then the residue waspartitioned between EtOAc (80 mL) and water (80 mL). The layers wereseparated and the aqueous layer was extracted with EtOAc (4×50 mL). Thecombined organics were dried over Na₂SO₄, filtered and evaporated toafford 2-((3-fluoropropyl)(methyl)amino)ethan-1-ol (3.95 g, 97%) as acolourless oil. ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.88 (2H, ddd), 2.27(3H, s), 2.51-2.62 (4H, m), 3.55-3.65 (2H, m), 4.47 (1H, t), 4.56 (1H,t).

N-(2-((3-chloro-5-fluoropyridin-2-yl)oxy)ethyl)-3-fluoro-N-methylpropan-1-amine

Sodium hydride (0.308 g, 7.69 mmol) was added to a solution of2-((3-fluoropropyl)(methyl)amino)ethan-1-ol (1.040 g, 7.69 mmol) in THF(26.8 mL). After stirring for 10 minutes, 3-chloro-2,5-difluoropyridine(1.00 g, 6.69 mmol) was added and stirring was continued for 1 hour. Thereaction was quenched by addition of water (50 mL) and extracted withEtOAc (2×50 mL). The combined organics were dried over MgSO₄, filteredand evaporated. The crude product was purified by flash silicachromatography, elution gradient 0 to 100% EtOAc in heptane. Productcontaining fractions were evaporated to dryness to affordN-(2-((3-chloro-5-fluoropyridin-2-yl)oxy)ethyl)-3-fluoro-N-methylpropan-1-amine(1.630 g, 92%) as a colourless liquid. ¹H NMR (500 MHz, CDCl₃, 27° C.)1.81-1.95 (2H, m), 2.36 (3H, s), 2.57-2.64 (2H, m), 2.83 (2H, t), 4.44(2H, t), 4.47 (1H, t), 4.57 (1H, t), 7.46 (1H, dd), 7.90 (1H, d). m/z:ES+ [M+H]+ 265.

3-fluoro-N-(2-((5-fluoro-3-methylpyridin-2-yl)oxy)ethyl)-N-methylpropan-1-amine

XPhos 2^(nd) generation precatalyst (0.122 g, 0.16 mmol) and potassiumcarbonate (1.720 g, 12.47 mmol) were added to a solution ofN-(2-((3-chloro-5-fluoropyridin-2-yl)oxy)ethyl)-3-fluoro-N-methylpropan-1-amine(1.65 g, 6.23 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane(0.436 mL, 3.12 mmol) in 1,4-dioxane (25.6 mL)/water (5.1 mL). Thereaction was degassed and heated to 90° C. for 6 hours. After cooling,the reaction was diluted with EtOAc (50 mL) and water (50 mL). Thelayers were separated and the aqueous was extracted with EtOAc (25 mL).The combined organics were dried over Na₂SO₄ and evaporated. The crudeproduct was purified by flash silica chromatography, elution gradient 20to 100% EtOAc in heptane. Product containing fractions were evaporatedto dryness to afford3-fluoro-N-(2-((5-fluoro-3-methylpyridin-2-yl)oxy)ethyl)-N-methylpropan-1-amine(1.50 g, 99%) as a light brown liquid. ¹H NMR (500 MHz, CDCl₃, 27° C.)1.82-1.94 (2H, m), 2.19 (3H, t), 2.35 (3H, s), 2.58-2.63 (2H, m), 2.81(2H, t), 4.38 (2H, t), 4.47 (1H, t), 4.56 (1H, t), 7.15-7.19 (1H, m),7.78-7.82 (1H, m). m/z: ES+ [M+H]+ 245.

5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylisonicotinaldehyde

LDA solution (2M, 3.84 mL, 7.68 mmol) was added to an oven-dried flaskcontaining3-fluoro-N-(2-((5-fluoro-3-methylpyridin-2-yl)oxy)ethyl)-N-methylpropan-1-amine(1.5 g, 6.14 mmol) in THF (20.0 mL). The reaction was stirred for 30minutes, then methyl formate (0.946 mL, 15.4 mmol) was then added andthe reaction was stirred for a further 30 minutes. The reaction wasquenched by addition of water (25 mL) and extracted with EtOAc (2×40mL). The combined organics were dried over MgSO₄ and evaporated. Thecrude product was purified by flash silica chromatography, elutiongradient 25 to 100% EtOAc in heptane. Product containing fractions wereevaporated to dryness to afford5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylisonicotinaldehydeas a pale yellow liquid, which was contaminated with unreacted startingmaterial in a 1:1 ratio. m/z: ES+ [M+H]+ 273.

Example 152(R)-3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid

Formaldehyde solution (37% vol, 0.021 mL, 0.29 mmol) was added to asolution of(R)-3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid (90 mg, 0.18 mmol) in DCM (1.5 mL). After stirring for 5 minutes,sodium triacetoxyhydroborate (61.0 mg, 0.29 mmol) was added and thereaction was stirred at room temperature for 1 hour. The reaction wasdiluted with DCM (10 mL) and washed with saturated aqueous sodiumchloride (10 mL). The layers were separated and the aqueous wasextracted with DCM (2×10 mL). The combined organics were dried overNa₂SO₄ and evaporated. The crude product was purified by preparativeHPLC (Waters XSelect CSH C18 column, 5μ silica, 19 mm diameter, 100 mmlength), using decreasingly polar mixtures of water (containing 1% NH₃)and MeCN as eluents. Fractions containing the desired compound wereevaporated to dryness to afford(R)-3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid (63.0 mg, 68%) as a colourless solid. ¹H NMR (500 MHz, CDCl₃, 27°C.) 1.03 (3H, d), 1.13 (3H, d), 1.70-1.96 (5H, m), 2.32 (3H, s),2.46-2.55 (1H, m), 2.55-2.60 (1H, m), 2.60-2.65 (2H, m), 2.68 (2H, dt),2.77 (1H, d), 2.96 (1H, ddd), 3.12-3.24 (1H, m), 3.64-3.79 (1H, m), 4.25(1H, ddd), 4.37 (1H, t), 4.47 (1H, t), 4.64 (1H, dt), 5.25 (1H, s),7.02-7.17 (2H, m), 7.19 (1H, dd), 7.50 (1H, dd), 7.58 (1H, s), 7.86 (1H,s), 9.62 (1H, s); m/z: ES+ [M+H]+ 515.

Example 155(2R)-3-[(1R,3R)-6-fluoro-1-[5-fluoro-2-[2-[3-fluoropropyl(methyl)amino]ethoxy]-3-methyl-4-pyridyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-methyl-propanoicacid

2M sodium hydroxide solution (1.17 mL, 2.34 mmol) was added to a stirredsolution of methyl(R)-3-((1R,3R)-6-fluoro-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(426 mg, 0.47 mmol) in THF (4 mL) and MeOH (2 mL) at 21° C. Theresulting mixture was stirred at 21° C. for 16 hours. The mixture wasconcentrated under reduced pressure. Water (5 mL) and AcOH (1 mL) wereadded and the resulting mixture was extracted with DCM (3×15 mL). Thecombined organics were dried (phase separation cartridge) andconcentrated under reduced pressure to give the crude product which waspurified successively by preparative HPLC (Puriflash C18, 15μ silica, 35g), using decreasingly polar mixtures of water (containing 0.1% formicacid) and MeCN as eluents followed by preparative HPLC (Waters CSH C18OBD column, 5μ silica, 30 mm diameter, 100 mm length), usingdecreasingly polar mixtures of water (containing 1% NH₃) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford(2R)-3-((1R,3R)-6-fluoro-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid (45.0 mg, 18%) as an off-white solid. ¹H NMR (500 MHz, DMSO, 27°C.) 0.94 (3H, d), 1.01 (3H, d), 1.69-1.86 (5H, m), 2.22 (3H, s),2.40-2.49 (4H, m), 2.56-2.71 (5H, m), 2.95 (1H, dd), 3.59-3.70 (1H, m),4.25-4.31 (2H, m), 4.43 (2H, dt), 5.13 (1H, s), 6.83 (1H, td), 7.12-7.20(2H, m), 8.00 (1H, s), 10.49 (1H, s); m/z: ES+ [M+H]+ 533.

Procedures used to prepare the starting material methyl(R)-3-((1R,3R)-6-fluoro-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoateare described below.

Methyl(R)-3-((1R,3R)-6-fluoro-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate

A solution of methyl(R)-3-(((R)-1-(5-fluoro-1H-indol-3-yl)propan-2-yl)amino)-2-methylpropanoate(200 mg, 0.68 mmol) and5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylisonicotinaldehyde(484 mg, 0.89 mmol) in toluene (3 mL) and acetic acid (0.33 mL) washeated at 95° C. for 16 hours. The resulting mixture was concentratedunder reduced pressure and the residue was dissolved in EtOAc (50 mL)and washed with saturated aqueous NaHCO₃ (25 mL). The aqueous phase wasextracted with EtOAc (50 mL) and the combined organics were dried overNa₂SO₄ and concentrated under reduced pressure. The crude product waspartially purified by flash silica chromatography, eluting with EtOAc.Fractions containing the desired product were evaporated to dryness toafford methyl(R)-3-((1R,3R)-6-fluoro-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(426 mg, >100%) as a yellow gum. Taken onto the next step withoutfurther purification.

Example 156 Preparation of3-((1R,3R)-6-fluoro-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propanoicacid

2N NaOH solution (0.563 mL, 1.13 mmol) was added to a solution of methyl3-((1R,3R)-6-fluoro-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propanoate(120 mg, 0.23 mmol) in THF (1.0 mL)/MeOH (1.0 mL). The reaction wasstirred at room temperature for 2 hours, then was diluted with EtOAc (20mL) and water (20 mL). The pH was adjusted to ˜5 by addition of 2N HClsolution and the layers were separated. The aqueous layer was extractedwith EtOAc (2×10 mL), then the combined organics were dried over Na₂SO₄and evaporated. The crude product was purified by flash silicachromatography, elution gradient 0 to 20% MeOH in DCM. Productcontaining fractions were evaporated to dryness to afford3-((1R,3R)-6-fluoro-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propanoicacid (82 mg, 70%) as a beige solid. ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.10(3H, d), 1.88 (3H, s), 1.89-1.93 (2H, m), 2.10-2.38 (2H, m), 2.43 (3H,s), 2.66 (2H, d), 2.76 (2H, s), 2.81-2.93 (2H, m), 2.98-3.07 (1H, m),3.11 (1H, d), 3.63 (1H, s), 4.22-4.36 (1H, m), 4.36-4.41 (1H, m), 4.47(1H, s), 4.57-4.69 (1H, m), 5.29 (1H, s), 6.83 (1H, t), 7.11 (2H, t),7.81 (1H, s), 11.71 (1H, s). (1×exchangeable not observed.) m/z: ES+[M+H]+ 519.

Procedures used to prepare the starting material methyl3-((1R,3R)-6-fluoro-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propanoateare described below.

Methyl (R)-3-((1-(5-fluoro-1H-indol-3-yl)propan-2-yl)amino)propanoate

Methyl acrylate (95 μl, 1.05 mmol) was added to a solution of(R)-1-(5-fluoro-1H-indol-3-yl)propan-2-amine (192 mg, 1.0 mmol) in MeOH(0.40 mL). The reaction was stirred at room temperature for 2 hours. Thevolatiles were evaporated, then the crude product was purified by flashsilica chromatography, elution gradient 0 to 10% MeOH in DCM. Productcontaining fractions were evaporated to dryness to afford methyl(R)-3-((1-(5-fluoro-1H-indol-3-yl)propan-2-yl)amino)propanoate (270 mg,97%) as a pale yellow liquid. ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.10 (3H,d), 2.36-2.53 (2H, m), 2.70-2.80 (2H, m), 2.80-2.90 (1H, m), 2.91-3.06(2H, m), 3.57 (3H, s), 6.93 (1H, td), 7.09 (1H, d), 7.23 (1H, dd),7.25-7.30 (1H, m), 8.04 (1H, s). (×exchangeable not observed.) m/z: ES+[M+H]+ 279.

Methyl3-((1R,3R)-6-fluoro-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propanoate

Methyl (R)-3-((1-(5-fluoro-1H-indol-3-yl)propan-2-yl)amino)propanoate(139 mg, 0.50 mmol) and5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylisonicotinaldehyde(65% weight, 209 mg, 0.50 mmol) were heated to 90° C. in toluene (2.25mL)/acetic acid (0.25 mL) overnight. After cooling, the volatiles wereevaporated. The residue was dissolved in DCM (20 mL) and washed withsaturated aqueous NaHCO₃ (20 mL). The aqueous layer was extracted withDCM (20 mL), then the combined organics were dried over Na₂SO₄ andevaporated. The crude product was purified by preparative HPLC (WatersXSelect CSH C18 column, 5μ silica, 19 mm diameter, 100 mm length), usingdecreasingly polar mixtures of water (containing 1% NH₃) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford methyl3-((1R,3R)-6-fluoro-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propanoate(134 mg, 50%) as a pale yellow gum. ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.09(3H, d), 1.74-1.87 (2H, m), 1.88 (3H, s), 2.30 (3H, s), 2.30-2.40 (2H,m), 2.53 (2H, t), 2.64 (1H, d), 2.67-2.73 (1H, m), 2.73-2.77 (2H, m),2.91 (1H, dt), 3.08 (1H, ddd), 3.56 (3H, s), 3.59-3.67 (1H, m), 4.33(2H, t), 4.39 (1H, t), 4.49 (1H, t), 5.27 (1H, s), 6.84 (1H, td), 7.09(1H, dd), 7.12 (1H, dd), 7.51 (1H, s), 7.85 (1H, s). m/z: ES+ [M+H]+533.

Example 157 Preparation of3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propanoicacid

2N NaOH solution (0.729 mL, 1.46 mmol) was added to a solution of methyl3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propanoate(150 mg, 0.29 mmol) in THF (1.0 mL)/MeOH (1.0 mL). The reaction wasstirred at room temperature for 2 hours, then was diluted with EtOAc (20mL) and water (20 mL). The pH was adjusted to ˜5 by addition of 2N HClsolution and the layers were separated. The aqueous layer was extractedwith EtOAc (2×10 mL), then the combined organics were dried over Na₂SO₄and evaporated. The crude product was purified by flash silicachromatography, elution gradient 0 to 20% MeOH in DCM. Productcontaining fractions were evaporated to dryness to afford3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propanoicacid (128 mg, 88%) as a beige solid. ¹H NMR (500 MHz, CDCl₃, 27° C.)1.14 (3H, d), 1.81-1.95 (5H, m), 2.18 (1H, dt), 2.35 (3H, s), 2.43 (1H,ddd), 2.63-2.74 (4H, m), 2.77 (1H, d), 2.87 (1H, dt), 3.00 (1H, ddd),3.19 (1H, ddd), 3.65 (1H, p), 4.26 (1H, ddd), 4.40 (1H, t), 4.49 (1H,t), 4.75 (1H, dt), 5.31 (1H, s), 7.09-7.16 (2H, m), 7.23 (1H, dd), 7.43(1H, s), 7.49-7.53 (1H, m), 7.89 (1H, s). (2×exchangeables notobserved.) m/z: ES+ [M+H]+ 501.

Procedures used to prepare the starting material methyl3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propanoateare described below.

Methyl (R)-3-((1-(1H-indol-3-yl)propan-2-yl)amino)propanoate

Methyl acrylate (0.284 mL, 3.15 mmol) was added to a solution of(R)-1-(1H-indol-3-yl)propan-2-amine (523 mg, 3.00 mmol) in MeOH (0.92mL). The reaction was stirred at room temperature for 2 hours. Thevolatiles were evaporated, then the crude product was purified by flashsilica chromatography, elution gradient 0 to 10% MeOH in DCM. Productcontaining fractions were evaporated to dryness to afford methyl(R)-3-((1-(1H-indol-3-yl)propan-2-yl)amino)propanoate (755 mg, 97%) as apale yellow liquid. ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.12 (3H, d),2.34-2.53 (2H, m), 2.68-2.91 (3H, m), 2.96 (1H, dt), 3.04 (1H, h), 3.55(3H, s), 7.05 (1H, d), 7.11 (1H, ddd), 7.19 (1H, ddd), 7.36 (1H, dt),7.59-7.66 (1H, m), 8.02 (1H, s). (1×exchangeable not observed.) m/z: ES+[M+H]+ 261.

Methyl3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propanoate

Methyl (R)-3-((1-(1H-indol-3-yl)propan-2-yl)amino)propanoate (156 mg,0.60 mmol) and5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylisonicotinaldehyde(65% weight, 251 mg, 0.60 mmol) were heated in toluene (4.50 mL)/aceticacid (0.50 mL) to 90° C. overnight. After cooling, the volatiles wereevaporated. The residue was dissolved in DCM (20 mL) and washed withsaturated aqueous NaHCO₃ solution (20 mL). The aqueous layer wasextracted with DCM (20 mL), then the combined organics were dried overNa₂SO₄ and evaporated. The crude product was purified by preparativeHPLC (Waters XSelect CSH C18 column, 5μ silica, 19 mm diameter, 100 mmlength), using decreasingly polar mixtures of water (containing 1% NH₃)and MeCN as eluents. Fractions containing the desired compound wereevaporated to dryness to afford methyl3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propanoate(164 mg, 53%) as a beige gum. ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.09 (3H,d), 1.72-1.86 (2H, m), 1.88 (3H, s), 2.29 (3H, s), 2.30-2.40 (2H, m),2.53 (2H, t), 2.63-2.73 (2H, m), 2.74 (2H, td), 2.92 (1H, dt), 3.11 (1H,ddd), 3.56 (3H, s), 3.59-3.67 (1H, m), 4.32 (2H, t), 4.39 (1H, t), 4.48(1H, t), 5.28 (1H, s), 7.00-7.15 (2H, m), 7.15-7.21 (1H, m), 7.49 (1H,dd), 7.55 (1H, s), 7.84 (1H, s); m/z: ES+ [M+H]+ 514.

Example 158 & 159 Preparation of3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butanoicacid

Ethyl 3-(((R)-1-(1H-indol-3-yl)propan-2-yl)amino)butanoate (216 mg, 0.75mmol) and5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylisonicotinaldehyde(314 mg, 0.75 mmol) were heated in toluene (3.375 mL)/acetic acid (0.375mL) to 100° C. overnight. After cooling, the volatiles were evaporated.The residue was dissolved in DCM (20 mL) and washed with saturatedaqueous NaHCO₃ (20 mL). The aqueous layer was extracted with DCM (20mL), then the combined organics were dried over Na₂SO₄ and evaporated.The crude product was purified by flash silica chromatography, elutiongradient 0 to 10% MeOH in EtOAc. Pure fractions were evaporated todryness to afford a pale yellow oil (˜250 mg) which was contaminatedwith unreacted starting material. The residue was dissolved in THF (1mL) and MeOH (1 mL), then 2N NaOH solution (1 mL) was added. Thereaction was stirred at room temperature overnight, then was dilutedwith EtOAc (10 mL) and water (10 mL). The aqueous was adjusted to pH 5by addition of 2N HCl and the layers were separated. The aqueous layerwas extracted with EtOAc (2×10 mL), then the combined organics weredried over Na₂SO₄ and evaporated. The crude product was purified bypreparative HPLC (Waters XSelect CSH C18 column, 5μ silica, 19 mmdiameter, 100 mm length), using decreasingly polar mixtures of water(containing 1% NH₃) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness to afford the two isomers,(3R)-3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butanoicacid and(3S)-3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butanoicacid:

Example 158; Isomer 1: 15.0 mg, 4% (as a colourless solid). ¹H NMR (500MHz, CDCl₃, 27° C.) 1.21 (3H, d), 1.25 (3H, d), 1.82 (3H, s), 1.85-1.93(2H, m), 2.26 (1H, dd), 2.33 (3H, s), 2.57-2.63 (2H, m), 2.67 (1H, d),2.73-2.82 (2H, m), 2.86 (1H, ddd), 3.12-3.19 (2H, m), 3.84-3.92 (1H, m),4.27-4.36 (1H, m), 4.39 (1H, t), 4.43-4.54 (2H, m), 5.73 (1H, s),7.01-7.16 (2H, m), 7.16-7.25 (1H, m), 7.42-7.55 (1H, m), 7.65 (1H, s),7.88 (1H, s). (1×exchangeable not observed.) m/z: ES+ [M+H]+ 515.

Example 159; Isomer 2: 35.0 mg, 9% (as a colourless solid). ¹H NMR (500MHz, CDCl₃, 27° C.) 1.17 (3H, d), 1.19 (3H, d), 1.79-1.91 (2H, m), 1.92(3H, s), 2.12 (1H, dd), 2.37 (3H, s), 2.63-2.79 (4H, m), 2.81-2.91 (2H,m), 3.05-3.14 (1H, m), 3.26 (1H, d), 3.83 (1H, dq), 4.32-4.41 (3H, m),4.47 (1H, q), 5.68 (1H, s), 7.10 (2H, tdt), 7.20 (1H, dd), 7.48 (1H,dd), 7.73 (1H, s), 7.86 (1H, s). (1×exchangeable not observed.) m/z: ES+[M+H]+ 515.

Procedures used to prepare the starting material ethyl3-(((R)-1-(1H-indol-3-yl)propan-2-yl)amino)butanoate are describedbelow.

Ethyl 3-(((R)-1-(1H-indol-3-yl)propan-2-yl)amino)butanoate

(R)-1-(1H-indol-3-yl)propan-2-amine (0.871 g, 5 mmol) and ethyl(E)-but-2-enoate (0.777 mL, 6.25 mmol) were stirred in MeOH (2.50 mL) at50° C. for 1 hour, then further heated to reflux and stirring wascontinued overnight. After cooling the volatiles were evaporated. Thecrude product was purified by flash silica chromatography, elutiongradient 25 to 100% EtOAc in heptane. Product containing fractions wereevaporated to dryness to afford ethyl3-(((R)-1-(1H-indol-3-yl)propan-2-yl)amino)butanoate (1.310 g, 91%) as apale yellow gum, as a 1:1 mixture of diastereoisomers. ¹H NMR (500 MHz,CDCl₃, 27° C.) 0.99-1.27 (9H, m), 2.18 (0.5H, dd), 2.30 (0.5H, dd), 2.41(1H, ddd), 2.75 (1H, dddd), 2.81-2.94 (1H, m), 3.12 (1H, hd), 3.25 (1H,dq), 4.11 (2H, p), 7.04 (1H, dd), 7.11 (1H, ddt), 7.18 (1H, tt), 7.35(1H, d), 7.52-7.70 (1H, m), 8.02 (1H, s). (1×exchangeable not observed.)m/z: ES+ [M+H]+ 289.

Example 160(R)-3-((1R,3R)-6-fluoro-1-(6-fluoro-3-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid

2M Sodium hydroxide (1 mL, 2.00 mmol) was added to a stirred solution ofmethyl(R)-3-((1R,3R)-6-fluoro-1-(6-fluoro-3-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(87 mg, 0.16 mmol) in THF (2 mL) and MeOH (1 mL). The resulting mixturewas stirred at 21° C. for 16 hours. The mixture was concentrated underreduced pressure then water (5 mL) and AcOH (1 mL) were added and theaqueous mixture was extracted with DCM (4×15 mL). The combined organicswere dried (phase separation cartridge) and concentrated under reducedpressure to give the crude product as a yellow gum which was purified bypreparative HPLC (Waters CSH C18 OBD column, 5μ silica, 30 mm diameter,100 mm length), using decreasingly polar mixtures of water (containing0.1% formic acid) and MeCN as eluents. Fractions containing the desiredcompound were evaporated under reduced pressure, redissolved in 1Mammonia in MeOH (1 mL) and concentrated under reduced pressure to give(R)-3-((1R,3R)-6-fluoro-1-(6-fluoro-3-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid (32.0 mg, 38%) as a pale yellow solid. ¹H NMR (500 MHz, DMSO, 27°C.) 0.99 (3H, d), 1.07 (3H, d), 1.72-1.95 (5H, m), 2.27 (3H, s),2.30-2.38 (1H, m), 2.51 (2H, t), 2.64-2.72 (1H, m), 2.73 (2H, t), 3.02(1H, dd), 3.23 (3H, s), 3.64-3.73 (1H, m), 4.03 (2H, ddt), 4.49 (2H,dt), 5.24 (1H, s), 6.86 (1H, td), 6.97-7.14 (2H, m), 7.14-7.25 (2H, m),10.40 (1H, s); m/z: ES+ [M+H]+ 532.

Procedures used to prepare the starting material methyl(R)-3-((1R,3R)-1-(3-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoateare described below.

Methyl(R)-3-((1R,3R)-1-(3-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate

RockPhos 3^(rd) generation catalyst (31.2 mg, 0.04 mmol) was added to adegassed mixture of methyl(R)-3-((1R,3R)-1-(3-bromo-6-fluoro-2-methylphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(181 mg, 0.37 mmol), tert-butyl(3-fluoropropyl)(2-hydroxyethyl)carbamate (163 mg, 0.74 mmol) and cesiumcarbonate (360 mg, 1.11 mmol) in toluene (2 mL) at 21° C. The resultingmixture was heated at 90° C. for 6 hours. The mixture was allowed tocool to room temperature and diluted with EtOAc (25 mL) and water (25mL). The layers were separated and the aqueous layer was extracted withEtOAc (2×25 mL). The combined organics were dried (phase separationcartridge) and concentrated to give the crude product as a brown gumwhich was purified by flash silica chromatography, elution gradient 0 to60% EtOAc in heptane. Product containing fractions were evaporated todryness to afford methyl(R)-3-((1R,3R)-1-(3-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-6-fluoro-3-methyhyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(108 mg, 46%) as a pale yellow foam. ¹H NMR (500 MHz, CDCl₃, 27° C.)1.02 (3H, d), 1.09 (3H, d), 1.40-1.48 (9H, m), 1.81 (3H, s), 1.84-1.94(2H, m), 2.52-2.67 (4H, m), 3.04-3.12 (1H, m), 3.35-3.46 (2H, m), 3.50(3H, s), 3.52-3.59 (2H, m), 3.64-3.72 (1H, m), 4.03 (2H, s), 4.41 (2H,d), 5.26 (1H, s), 6.73-6.86 (2H, m), 6.91 (1H, t), 7.04-7.13 (2H, m),7.23 (1H, s); ES+ [M+H]+ 632.

Methyl(R)-3-((1R,3R)-6-fluoro-1-(6-fluoro-3-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate

A solution of methyl(R)-3-((1R,3R)-1-(3-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(100 mg, 0.16 mmol) in formic acid (610 μL) was stirred at 40° C. for 1hour. The mixture was concentrated under reduced pressure and theresulting residue was dissolved in DCM (25 mL) and washed with saturatedaqueous NaHCO₃ (25 mL). The aqueous layer was extracted with DCM (25 mL)and the combined organics were evaporated to ˜10 mL in volume. To thissolution was added 37% w/w aqueous formaldehyde solution (23.55 μL, 0.24mmol) followed by sodium triacetoxyborohydride (51.8 mg, 0.24 mmol). Theresulting mixture was stirred at 21° C. for 1 hour. The reaction mixturewas diluted with DCM (10 mL) and washed with saturated aqueous NaHCO₃(20 mL). The aqueous layer was extracted with DCM (20 mL) and thecombined organics were dried over Na₂SO₄ and concentrated under reducedpressure. The crude product was taken immediately on to the next step.

Example 161 Preparation of(R)-3-((1R,3R)-1-(2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid

Lithium hydroxide monohydrate (9.0 mg, 0.22 mmol) was added to asolution of methyl(R)-3-((1R,3R)-1-(2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(0.011 g, 0.020 mmol) in tetrahydrofuran (0.2 mL), methanol (0.2 mL) andwater (0.2 mL). The resulting mixture was stirred at room temperaturefor 5 hours and then neutralized with aqueous hydrochloric acid (1N;0.21 mL, 0.21 mmol). The mixture was extracted with ethyl acetate, andthe extract was dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby flash silica chromatography, elution gradient 0 to 70% MeOH in DCM,to give(R)-3-((1R,3R)-1-(2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid (7.6 mg, 71%) as a pale yellow solid. ¹H NMR (500 MHz, DMSO-d₆, 27°C.) 1.03 (3H, d), 1.05 (3H, d), 1.72-1.88 (2H, m), 2.14-2.33 (6H, m),2.55-2.63 (5H, m), 2.75 (2H, br t), 2.83 (1H, br dd), 4.29-4.40 (2H, m),4.49 (2H, dt), 4.98 (1H, br s), 6.40 (1H, br d), 6.94-6.99 (1H, m),7.00-7.05 (1H, m), 7.22 (1H, d), 7.43 (1H, d), 7.82 (1H, br d), 10.39(1H, br s), 11.93-12.45 (1H, br s). (Two hydrogens not observed.) m/z:ES+ [M+H]+ 497.

Procedures used to prepare the starting material methyl(R)-3-((1R,3R)-1-(2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoateare described below.

Preparation of Methyl(R)-3-((1R,3R)-1-(2-chloro-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate

A mixture of methyl(R)-3-(((R)-1-(1H-indol-3-yl)propan-2-yl)amino)-2-methylpropanoate (0.85g, 3.1 mmol), 2-chloro-3-methylisonicotinaldehyde (0.50 g, 3.2 mmol) intoluene (10 mL) and acetic acid (1.0 mL) was stirred at 90° C. for 8hours. The reaction was allowed to cool to room temperature and was thenconcentrated under reduced pressure. The resulting residue was purifiedby flash silica chromatography, elution gradient 0 to 40% ethyl acetatein hexanes, to give methyl(R)-3-((1R,3R)-1-(2-chloro-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(0.75 g, 59%) as a pale yellow foam. ¹H NMR (300 MHz, DMSO-d₆, 27° C.)1.03 (6H, d), 2.33 (3H, br s), 2.40-2.48 (1H, m), 2.56-2.80 (3H, m),2.81-2.93 (1H, m), 3.35-3.48 (1H, m), 3.52 (3H, s), 4.98 (1H, s),6.82-7.09 (3H, m), 7.13-7.30 (1H, m), 7.44 (1H, d), 8.15 (1H, d), 10.34(1H, s). m/z: ES+ [M+H]+ 412.

Preparation of methyl(R)-3-((1R,3R)-1-(2-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate

A mixture of methyl(R)-3-((1R,3R)-1-(2-chloro-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(0.30 g, 0.73 mmol), tert-butyl(3-fluoropropyl)(2-hydroxyethyl)carbamate (0.209 g, 0.95 mmol), RockPhos3^(rd) Generation Precatalyst (0.031 g, 0.04 mmol) and cesium carbonate(0.593 g, 1.82 mmol) was evacuated and back-filled with nitrogen (3×).Toluene (3.5 mL) was added, and the mixture was again evacuated andback-filled with nitrogen (2×). The resulting suspension was stirred at90° C. for 24 hours, allowed to cool to room temperature, and filtered.The filtrate was concentrated under reduced pressure. The resultingresidue was purified by flash silica chromatography, elution gradient 0to 40% ethyl acetate in hexanes, to give crude product which was furtherpurified by SFC (Chialpak IB column, 250 mm length, 21.2 mm diameter, 5μm, 75 mL/min flow rate), eluting with 10% (0.2% NH₄OH methanol) in CO₂over 10 min, to give methyl(R)-3-((1R,3R)-1-(2-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(0.041 g, 9%) as a pale amber foam. ¹H NMR (500 MHz, DMSO-d₆, 27° C.)0.97-1.10 (6H, m), 1.30-1.47 (9H, m), 1.81-1.97 (2H, m), 2.19 (3H, brs), 2.54-2.66 (3H, m), 2.68-2.79 (1H, br m), 2.84 (1H, br d), 3.35-3.44(3H, m), 3.45-3.75 (2H, m), 3.51 (3H, s), 4.24-4.34 (1H, m), 4.34-4.47(1H, m), 4.46 (2H, dt), 4.93 (1H, br s), 6.45 (1H, br s), 6.93-6.99 (1H,m), 6.99-7.04 (1H, m), 7.21 (1H, d), 7.43 (1H, d), 7.84 (1H, br d),10.33 (1H, br s). m/z: ES+ [M+H]+ 597.

Preparation of methyl(R)-3-((1R,3R)-1-(2-(2-((3-fluoropropyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate

A solution of methyl(R)-3-((1R,3R)-1-(2-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(0.04 g, 0.07 mmol) in formic acid (1 mL, 26.07 mmol) was allowed tostand at room temperature for 18 hours and was then concentrated underreduced pressure. The residue was basified with saturated aqueous sodiumhydrogen carbonate, and extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The resulting residue was purified by flash silicachromatography, elution gradient 0 to 10% MeOH in DCM, to give methyl(R)-3-((1R,3R)-1-(2-(2-((3-fluoropropyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(0.030 g, 90%) as a clear film. ¹H NMR (500 MHz, DMSO-d₆, 27° C.)0.97-1.10 (6H, m), 1.74-1.86 (2H, m), 2.08-2.29 (3H, m), 2.57-2.64 (2H,m), 2.69 (2H, t), 2.71-2.78 (1H, m), 2.85 (1H, br dd), 2.90 (2H, t),3.39-3.47 (1H, m), 3.51 (3H, s), 4.25-4.34 (2H, m), 4.50 (2H, dt), 4.91(1H, s), 6.37-6.52 (1H, m), 6.93-6.98 (1H, m), 6.99-7.05 (1H, m), 7.21(1H, d), 7.42 (1H, d), 7.84 (1H, br d), 10.34 (1H, s). (Two hydrogensnot observed.); m/z: ES+ [M+H]+ 497.

Preparation of methyl(R)-3-((1R,3R)-1-(2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate

A solution of formaldehyde in water (37 wt %; 7.8 μL, 0.10 mmol) wasadded to a stirring solution of methyl(R)-3-((1R,3R)-1-(2-(2-((3-fluoropropyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(26 mg, 0.05 mmol) in dichloromethane (1 mL). Sodiumtriacetoxyborohydride (22 mg, 0.10 mmol) was then added and theresulting mixture was stirred at room temperature for 2 hours and thentreated with saturated aqueous sodium hydrogencarbonate and extractedwith dichloromethane. The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The resultingresidue was purified by flash silica chromatography, elution gradient 0to 10% MeOH in DCM, to give methyl(R)-3-((1R,3R)-1-(2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(14 mg, 52%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆, 27° C.)0.98-1.07 (6H, m), 1.74-1.88 (2H, m), 2.18 (3H, br s), 2.28 (3H, s),2.56-2.68 (3H, m), 2.68-2.78 (3H, m), 2.85 (1H, br dd), 3.39-3.47 (1H,m), 3.51 (3H, s), 4.29-4.40 (2H, m), 4.49 (2H, dt), 4.92 (1H, br s),6.45 (1H, br d), 6.93-6.98 (1H, m), 6.99-7.04 (1H, m), 7.21 (1H, d),7.42 (1H, d), 7.84 (1H, br d), 10.32 (1H, s). (Two hydrogens notobserved.); m/z: ES+ [M+H]+ 511.

Example 162 Preparation of(R)-3-((1R,3R)-1-(3-(2-((3,3-difluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid

Methyl(R)-3-((1R,3R)-1-(3-(2-((3,3-difluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(115 mg, 0.21 mmol) was dissolved in THF (0.8 mL)/MeOH (0.8 mL) andtreated with a solution of lithium hydroxide monohydrate (88 mg, 2.1mmol) in water (0.8 mL). The reaction was stirred at room temperaturefor 4.5 hours and then concentrated under reduced pressure. Theresulting residue was neutralized carefully with aqueous HCl (1N) to pH7, and the resulting mixture was extracted with EtOAc (2×). The combinedextracts were dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The resulting residue was purified bypreparative SFC (Chiralpak IC column, 5 μm, 21 mm diameter, 250 mmlength, 75 mL/min flow rate), eluting with 20% (0.2% NH₄OH in MeOH) inCO₂, to afford(R)-3-((1R,3R)-1-(3-(2-((3,3-difluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid (41 mg, 37%) as a beige dry film. ¹H NMR (500 MHz, DMSO-d₆, 27° C.)0.91 (3H, d), 0.99 (3H, d), 1.63-2.04 (5H, m), 2.17-2.33 (1H, m),2.51-2.57 (2H, m), 2.62 (br 1H, d), 2.67 (2H, t), 2.72-2.89 (2H, m),2.92-3.00 (1H, m), 3.53-3.70 (1H, m), 3.78-3.93 (1H, m), 3.93-4.04 (1H,m), 5.16 (1H, s), 6.07 (1H, tt), 6.78 (1H, td), 6.87-6.98 (1H, m),6.99-7.07 (1H, m), 7.07-7.23 (2H, m), 10.34 (1H, s). (Two hydrogens notobserved.); m/z: ES+ [M+H]+ 536.

Procedures used to prepare the starting material methyl(R)-3-((1R,3R)-1-(3-(2-((3,3-difluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoateare described below.

Preparation of methyl(R)-3-((1R,3R)-6-fluoro-1-(6-fluoro-3-(2-hydroxyethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate

Methyl(R)-3-((1R,3R)-1-(3-bromo-6-fluoro-2-methylphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(330 mg, 0.67 mmol), cesium carbonate (547 mg, 1.68 mmol), and2-((tert-butyldimethylsilyl)oxy)ethan-1-ol (178 mg, 1.01 mmol) weresuspended in toluene (3.5 mL). The reaction flask was then evacuated andback-filled with nitrogen (3×) before the addition of RockPhos 3^(rd)Generation Precatalyst (30 mg, 0.03 mmol). The reaction flask was againevacuated and back-filled with nitrogen (3×) before being heated at 90°C. for 2 hrs. The reaction was cooled to room temperature, diluted withDCM (25 mL), and washed with saturated aqueous sodium chloride (25 mL).The aqueous layer was extracted with DCM (25 mL), and the combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The resulting residue was dissolvedin THF (3.5 mL) and treated with TBAF (1.0 M in THF; 2 mL). After 30minutes, the reaction was diluted with EtOAc (25 mL), washed withsaturated aqueous sodium chloride (25 mL), and the organic layer wasdried over sodium sulfate, filtered and concentrated under reducedpressure. The resulting residue was purified by flash silicachromatography, elution gradient 0 to 80% EtOAc in hexanes. Productfractions were concentrated under reduced pressure to afford methyl(R)-3-((1R,3R)-6-fluoro-1-(6-fluoro-3-(2-hydroxyethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(130 mg, 39%) as a brown solid. ¹H NMR (500 MHz, DMSO-d₆, 27° C.) 0.91(3H, d), 0.98 (3H, d), 1.55-1.91 (3H, m), 2.42-2.65 (4H, m), 2.85-2.98(1H, m), 3.41 (3H, s), 3.57-3.71 (3H, m), 3.77-3.99 (2H, m), 4.76 (1H,t), 5.11 (1H, s), 6.72-6.83 (1H, m), 6.89-7.06 (2H, m), 7.07-7.19 (2H,m), 10.33 (1H, s). m/z: ES+ [M+H]+ 473.

Preparation of methyl(R)-3-((1R,3R)-6-fluoro-1-(6-fluoro-2-methyl-3-(2-((methylsulfonyl)oxy)ethoxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate

Methanesulfonyl chloride (0.022 mL, 0.28 mmol) was added to a solutionof methyl(R)-3-((1R,3R)-6-fluoro-1-(6-fluoro-3-(2-hydroxyethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(121 mg, 0.26 mmol), DIPEA (0.056 mL, 0.32 mmol), and DCM (2.5 mL). Thereaction was stirred at room temperature for 20 minutes and then dilutedwith DCM (10 mL) and washed with saturated aqueous sodium chloride. Theorganic layer was dried over sodium sulfate, filtered, and concentratedunder reduced pressure to afford crude methyl(R)-3-((1R,3R)-6-fluoro-1-(6-fluoro-2-methyl-3-(2-((methylsulfonyl)oxy)ethoxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(141 mg, 100%) as a yellow foam. m/z: ES+ [M+H]+ 551.

Preparation of methyl(R)-3-((1R,3R)-1-(3-(2-((3,3-difluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate

Methyl (R)-3-((1R,3R)-6-fluoro-1-(6-fluoro-2-methyl-3-(2-((methylsulfonyl)oxy)ethoxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(141 mg, 0.26 mmol), 3,3-difluoropropan-1-amine hydrochloride (67 mg,0.51 mmol), potassium carbonate (106 mg, 0.77 mmol), and potassiumiodide (42.5 mg, 0.26 mmol) were suspended in acetonitrile (2.5 mL) andheated at 80° C. for 17 hours. The reaction was cooled to roomtemperature, diluted with EtOAc, and washed with saturated aqueoussodium chloride. The aqueous layer was extracted with EtOAc, and thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedby flash silica chromatography, elution gradient 0 to 20% MeOH in DCM.Product fractions were concentrated under reduced pressure to affordmethyl(R)-3-((1R,3R)-1-(3-(2-((3,3-difluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoate(119 mg, 85%) as a beige foam. m/z: ES+ [M+H]+ 550.

Example 163 Preparation of3-((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propanoicacid

NaOH solution (0.82 mL, 1.65 mmol) was added to a solution of methyl3-((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propanoate(170 mg, 0.33 mmol) in THF (1.24 mL)/MeOH (1.24 mL). The reaction wasstirred at room temperature for 2 hours, then was neutralised byaddition of 2N HCl solution. The volatiles were evaporated, then thecrude product was purified by preparative HPLC (Waters XSelect CSH C18ODB column, 5μ silica, 30 mm diameter, 100 mm length), usingdecreasingly polar mixtures of water (containing 1% NH₃) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford3-((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propanoicacid (145 mg, 88%) as a colourless solid. ¹H NMR (500 MHz, CDCl₃, 27°C.) 1.23 (3H, d), 1.85 (2H, ddt), 1.87 (3H, s), 2.16 (1H, d), 2.32 (3H,s), 2.48-2.56 (1H, m), 2.58 (2H, t), 2.66-2.88 (3H, m), 2.89-2.96 (2H,m), 3.27 (1H, ddd), 3.76 (1H, p), 4.03 (2H, dp), 4.42 (1H, t), 4.52 (1H,t), 5.40 (1H, s), 6.83 (1H, dd), 6.94 (1H, t), 7.09-7.19 (2H, m), 7.22(1H, dd), 7.38 (1H, s), 7.51 (1H, dd). (1×exchangeable not observed.);m/z: ES+ [M+H]+ 500.

Procedures used to prepare the starting material methyl3-((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propanoateare described below.

2-(3-Bromo-6-fluoro-2-methylphenyl)-1,3-dioxolane

3-Bromo-6-fluoro-2-methylbenzaldehyde (4.8 g, 22.12 mmol) was added toethane-1,2-diol (4.12 g, 66.35 mmol) and 4-methylbenzenesulfonic acid(0.381 g, 2.21 mmol) in toluene (100 mL). The resulting mixture wasstirred at 100° C. for 16 hours. The reaction mixture was poured intosaturated NaHCO₃ solution (50 mL), extracted with EtOAc (2×50 mL), thenthe organic layer was dried over Na₂SO₄, filtered and evaporated toafford a yellow gum which was purified by flash silica chromatography,elution gradient 0 to 20% EtOAc in petroleum ether. Pure fractions wereevaporated to dryness to afford2-(3-bromo-6-fluoro-2-methylphenyl)-1,3-dioxolane (5.00 g, 87%) as acolourless oil. ¹H NMR (300 MHz, CDCl₃, 27° C.) 2.50 (3H, s), 3.94-4.14(2H, m), 4.10-4.30 (2H, m), 6.16 (1H, s), 6.74-6.87 (1H, m), 7.47-7.58(1H, m).

Tert-butyl(2-(3-(1,3-dioxolan-2-yl)-4-fluoro-2-methylphenoxy)ethyl)(3-fluoropropyl)carbamate

Tert-butyl (3-fluoropropyl)(2-hydroxyethyl)carbamate (5.08 g, 23.0 mmol)was added to 2-(3-bromo-6-fluoro-2-methylphenyl)-1,3-dioxolane (5.00 g,19.2 mmol), Cs₂CO₃ (18.72 g, 57.45 mmol) and rockphos 3^(rd) generationprecatalyst (0.801 g, 0.96 mmol) in toluene (12 mL) under nitrogen. Theresulting mixture was stirred at 80° C. for 16 hours. The solvent wasremoved under reduced pressure then the reaction mixture was dilutedwith EtOAc (50 mL), and washed sequentially with saturated aqueousNaHCO₃ (2×20 mL), water (20 mL), and saturated aqueous sodium chloride(20 mL). The organic layer was dried over Na₂SO₄, filtered andevaporated. The crude product was purified by flash C18-flashchromatography, elution gradient 0 to 80% MeCN in water. Pure fractionswere evaporated to dryness to afford tert-butyl(2-(3-(1,3-dioxolan-2-yl)-4-fluoro-2-methylphenoxy)ethyl)(3-fluoropropyl)carbamate(4.80 g, 62%) as a yellow gum. ¹H NMR (300 MHz, CDCl₃, 27° C.) 1.45 (9H,s), 1.85-2.11 (2H, m), 2.29 (3H, s), 3.46 (2H, t), 3.57-3.64 (2H, m),3.94-4.09 (4H, m), 4.17-4.29 (2H, m), 4.40 (1H, t), 4.55 (1H, t), 6.15(1H, s), 6.70-6.90 (2H, m). m/z (ES+), [M-tBu]+=346.

Tert-butyl(2-(4-fluoro-3-formyl-2-methylphenoxy)ethyl)(3-fluoropropyl)carbamate

4-Methylbenzenesulfonic acid (0.244 g, 1.42 mmol) was added totert-butyl(2-(3-(1,3-dioxolan-2-yl)-4-fluoro-2-methylphenoxy)ethyl)(3-fluoropropyl)carbamate(5.70 g, 14.2 mmol) in acetone (80 mL). The resulting mixture wasstirred at room temperature for 16 hours. The reaction mixture waspoured into saturated aqeuous NaHCO₃ (50 mL), extracted with EtOAc (2×50mL), then the organic layer was dried over Na₂SO₄, filtered andevaporated to afford a yellow gum which was purified by flash silicachromatography, elution gradient 0 to 20% EtOAc in petroleum ether.Product containing fractions were evaporated to dryness to affordtert-butyl(2-(4-fluoro-3-formyl-2-methylphenoxy)ethyl)(3-fluoropropyl)carbamate(3.40 g, 67%) as a yellow gum, which solidified on standing. ¹H NMR (400MHz, CDCl₃, 27° C.) 1.47 (9H, s), 1.86-2.10 (2H, m), 2.50 (3H, s), 3.48(2H, t), 3.60-3.74 (2H, m), 3.99-4.15 (2H, m), 4.44 (1H, t), 4.55 (1H,t), 6.81-7.16 (2H, m), 10.51 (1H, s). m/z (ES+), [M-Boc]=258.

Methyl3-((1R,3R)-1-(3-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propanoate

Methyl (R)-3-((1-(1H-indol-3-yl)propan-2-yl)amino)propanoate (260 mg,1.0 mmol) and tert-butyl(2-(4-fluoro-3-formyl-2-methylphenoxy)ethyl)(3-fluoropropyl)carbamate(357 mg, 1.00 mmol) were heated in toluene (3.60 mL)/acetic acid (0.40mL) to 100° C. for 6 hours. After cooling, the volatiles were evaporatedand the residue was dissolved in DCM (20 mL) and washed with saturatedaqueous NaHCO₃ (20 mL). The aqueous layer was extracted with DCM (20mL), then the combined organics were dried over Na₂SO₄ and evaporated.The crude product was purified by flash silica chromatography, elutiongradient 0 to 40% EtOAc in heptane. Product containing fractions wereevaporated to dryness to afford methyl3-((1R,3R)-1-(3-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propanoate(301 mg, 50%) as a beige solid. m/z: ES+ [M+H]+ 600.

Methyl3-((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propanoate

Methyl3-((1R,3R)-1-(3-(2-((tert-butoxycarbonyl)(3-fluoropropyl)amino)ethoxy)-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propanoate(280 mg, 0.47 mmol) was stirred in formic acid (2.33 mL) at 40° C. for 1hour. The volatiles were evaporated, then the residue was dissolved inDCM (20 mL) and washed with saturated aqueous NaHCO₃ (20 mL). Theaqueous layer was extracted with DCM (10 mL), then the combined organicswere dried over Na₂SO₄ and evaporated to a volume of ˜10 mL. To thissolution was added 37% formaldehyde solution (71.9 mg, 0.70 mmol),followed by sodium triacetoxyborohydride (97 mg, 0.70 mmol). Thereaction was stirred at room temperature for 1 hour, then was dilutedwith DCM (10 mL) and washed with saturated aqueous NaHCO₃ solution (20mL). The aqueous layer was extracted with DCM (20 mL), then the combinedorganics were dried over Na₂SO₄ and evaporated. The crude product waspurified by preparative HPLC (Waters XSelect CSH C18 ODB column, 5μsilica, 30 mm diameter, 100 mm length), using decreasingly polarmixtures of water (containing 1% NH₃) and MeCN as eluents. Fractionscontaining the desired compound were evaporated to dryness to affordmethyl3-((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propanoate(180 mg, 75%) as a beige solid. ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.00(3H, d), 1.72 (2H, ddd), 1.78 (3H, s), 2.11-2.19 (2H, m), 2.19 (3H, s),2.44 (2H, t), 2.59 (1H, d), 2.61-2.68 (3H, m), 2.79 (1H, dt), 3.02 (1H,ddd), 3.44 (3H, s), 3.49-3.56 (1H, m), 3.87 (2H, tt), 4.30 (1H, t), 4.39(1H, t), 5.24 (1H, s), 6.68 (1H, dd), 6.80 (1H, t), 6.91-7.00 (2H, m),7.00-7.07 (1H, m), 7.23 (1H, s), 7.38 (1H, dd). m/z: ES+ [M+H]+ 514.

Examples 16-56, 58-116, 118-120, 122-123, 125, 128-142, 144, 146-151 and153-154 (Table G below) were prepared using methods analogous to thosedescribed above.

TABLE G Ex- LCMS ample Structure Name 1H NMR [M + H]+ 16

3-fluoro-N-(2- (3-((1R,3R)-3- methyl-2- (2,2,2- trifluoroethyl)-2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1- yl)phenoxy)ethyl)propan-1- amine ¹H NMR (300 MHz, DMSO-d_(6,) 27° C.) 1.11 (3H, d),1.59- 1.92 (3H, m), 2.54- 2.71 (4H, m), 2.82 (2H, br t), 2.91-3.05 (1H,m), 3.07-3.20 (1H, m), 3.57 (1H, dq), 3.94 (2H, br t), 4.47 (2H, dt),4.97 (1H, s), 6.74 (1H, br s), 6.79-6.89 (2H, m), 6.95-7.02 (1H, m),7.04-7.11 (1H, m), 7.25 (1H, t), 7.30 464 (1H, d), 7.45 (1H, d), 10.83(1H, s). 17

3-fluoro-N-(2- (4-methyl-3- ((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)phenoxy) ethyl)propan-1- amine ¹H NMR (300 MHz, DMSO-d₆, 27° C.) 1.07(3H, d), 1.52- 1.83 (3H, m), 2.34 (3H, s), 2.52-2.59 (2H, m), 2.63 (1H,br dd), 2.69-2.83 (3H, m), 2.99 (1H, dq), 3.28-3.37 (1H, m), 3.47 (1H,dq), 3.82 (2H, t), 4.43 (2H, dt), 5.09 (1H, s), 6.22 (1H, br s), 6.78(1H, dd), 6.95-7.02 (1H, m), 7.02-7.08 (1H, 478 m), 7.12 (1H, d),7.22-7.29 (1H, m), 7.45 (1H, d), 10.57 (1H, s). 18

3-fluoro-N-(2- (3-methyl-5- ((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)phenoxy) ethyl)propan-1- amine ¹H NMR (300 MHz, DMSO-d₆, 27° C.) 1.11(3H, d), 1.64- 1.88 (3H, m), 2.23 (3H, s), 2.53-2.70 (4H, m), 2.81 (2H,t), 2.89-3.06 (1H, m), 3.07-3.23 (1H, m), 3.55 (1H, dq), 3.92 (2H, t),4.47 (2H, dt), 4.92 (1H, s), 6.54- 6.60 (1H, m), 6.60- 6.64 (1H, m),6.66- 6.71 (1H, m), 6.95- 7.02 (1H, m), 7.03- 478 7.11 (1H, m), 7.27-7.33 (1H, m), 7.44 (1H, d), 10.80 (1H, s). 19

3-fluoro-N-(2- (2-methyl-5- ((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)phenoxy) ethyl)propan-1- amine ¹H NMR (300 MHz, DMSO-d_(6,) 27° C.)1.11 (3H, d), 1.61- 1.90 (3H, m), 2.13 (3H, s), 2.55-2.72 (4H, m), 2.86(2H, t), 2.92-3.07 (1H, m), 3.09-3.24 (1H, m), 3.54 (1H, dq), 3.90 (2H,t), 4.49 (2H, dt), 4.95 (1H, s), 6.63 (1H, d), 6.91 (1H, s), 6.94-7.01(1H, m), 7.02-7.10 (2H, m), 7.29 (1H, d), 7.44 478 (1H, d), 10.77 (1H,s). 20

3-fluoro-N-(2- (2-methyl-3- ((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)phenoxy) ethyl)propan-1- amine ¹H NMR (300 MHz, DMSO-d₆, 27° C.) 1.07(3H, d), 1.65- 1.96 (3H, m), 2.29 (3H, s), 2.56-2.86 (4H, m), 2.91 (2H,t), 2.90-3.10 (1H, m), 3.28-3.37 (1H, m), 3.37-3.57 (1H, m), 4.00 (2H,t), 4.52 (2H, dt), 5.15 (1H, s), 6.29 (1H, br d), 6.90 (1H, d), 6.94-7.09 (3H, m), 7.20- 7.28 (1H, m), 7.44 478 (1H, d), 10.53 (1H, s). 21

N-(2-(4-ethyl- 3-((1R,3R)-3- methyl-2- (2,2,2- trifluoroethyl)- 2,3,4,9-tetrahydro-1H- pyrido[3,4- b]indol-1- yl)phenoxy) ethyl)-3-fluoropropan- 1-amine ¹H NMR (300 MHz, DMSO-d₆, 27° C.) 1.07 (3H, d),1.15 (3H, t), 1.61-1.78 (3H, m), 2.52-2.56 (2H, m), 2.63-2.85 (6H, m),2.90-3.10 (1H, m), 2.90-3.10 (1H, m), 3.39-3.58 (1H, m), 3.81 (2H, t),4.42 (2H, dt), 5.16 (1H, s), 6.14 (1H, br s), 6.84 (1H, dd), 6.96-7.02(1H, m), 7.02-7.08 (1H, m), 492 7.17 (1H, d), 7.24- 7.28 (1H, m), 7.46(1H, d), 10.61 (1H, s). 22

N-(2-(4- chloro-3- ((1R,3R)-3- methyl-2- (2,2,2- trifluoroethyl)-2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1- yl)phenoxy) ethyl)-3-fluoropropan- 1-amine ¹H NMR (300 MHz, DMSO-d₆, 27° C.) 1.10 (3H, d),1.60- 1.77 (3H, m), 2.58- 2.77 (3H, m), 2.83 (1H, dd), 2.92-3.10 (1H,m), 3.31-3.41 (1H, m), 3.51 (1H, br dq), 3.83 (2H, t), 4.41 (2H, dt),5.32 (1H, s), 6.30 (1H, d), 6.94 (1H, dd), 6.96- 7.03 (1H, m), 7.03-7.09 (1H,m), 7.21- 7.29 (1H, m), 7.42 498 (1H, d), 7.47 (1H, d), 10.62(1H, s). (Two hydrogen multiplet obscured by DMSO). 23

4-(2-((3- fluoropropyl) amino)ethoxy)- 2-((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)benzonitrile ¹H NMR (300 MHz, Methanol-d4, 27° C.) 1.08 (3H, d),1.59- 1.91 (2H, m), 2.51- 2.70 (3H, m), 2.81 (2H, t), 2.80-2.96 (1H, m),3.04 (1H, dd), 3.27-3.38 (1H, obsc m), 3.40-3.52 (1H, m), 3.95 (2H, t),4.35 (2H, dt), 5.11 (1H, s), 6.79 (1H, d), 6.85-7.00 (3H, m), 7.08-7.16(1H, m), 7.27-7.42 (1H, m), 489 7.60 (1H, d). (2 exchangeables notobserved). 24

3-fluoro-N-(2- (2-fluoro-3- ((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)phenoxy) ethyl)propan-1- amine ¹H NMR (300 MHz, DMSO-d₆, 27° C.) 1.09(3H, d), 1.66- 1.95 (3H, m), 2.55- 2.80 (4H, m), 2.92 (2H, t), 2.91-3.01(1H, m), 3.17-3.32 (1H, m), 3.53 (1H, dq), 4.09 (2H, t), 4.52 (2H, dt),5.32 (1H, s), 6.18-6.26 (1H, m), 6.89-7.17 (4H, m), 7.20-7.30 (1H, m),7.46 (1H, d), 10.69 (1H, s). 482 25

N-(2-(2- chloro-3- ((1R,3R)-3- methyl-2- (2,2,2- trifluoroethyl)-2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1- yl)phenoxy) ethyl)-3-fluoropropan- 1-amine ¹H NMR (300 MHz, DMSO-d₆, 27° C.) 1.09 (3H, d),1.67- 1.96 (3H, m), 2.64 (1H, d), 2.72 (2H, t), 2.83 (1H, br dd),2.90-3.08 (3H, m), 3.33-3.42 (1H, m), 3.51 (1H, dq), 4.02- 4.19 (2H, m),4.53 (2H, dt), 5.41 (1H, s), 6.40 (1H, dd), 6.94-7.17 (4H, m), 7.20-7.26(1H, m), 7.46 (1H, d), 10.59 498 (1H, s). 26

3-fluoro-N-(2- (4-methoxy-2- methyl-3- ((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)phenoxy) ethyl)propan-1- amine ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.17(3H, d), 1.78-1.84 (1H, m), 1.86-1.89 (4H, m), 2.70 (1H, d), 2.76 (2H,t), 2.84- 2.99 (3H, m), 3.12 (1H, dt), 3.24 (1H, ddd), 3.66-3.74 (1H,m), 3.84 (3H, s), 3.92-4.01 (2H, m), 4.44 (1H, t), 4.53 (1H, t), 5.73(1H, s), 6.76 (1H, d), 6.85 (1H, d), 7.05-7.11 508 (2H, m), 7.15-7.19(1H, m), 7.24 (1H, s), 7.48 (1H, dt). (1 exchangeable not observed). 27

3-fluoro-N-(2- (3-fluoro-4- methoxy-5- ((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)phenoxy) ethyl)propan-1- amine ¹H NMR (300 MHz, DMSO-d₆, 27° C.) 1 11(3H, d), 1.55- 1.81 (3H, m), 2.56- 2.82 (4H, m), 2.86- 3.08 (1H, m),3.35- 3.25 (1H, m), 3.51 (1H, dq), 3.80 (2H, t), 3.87 (3H, s), 4.41 (2H,dt), 5.32 (1H, s), 5.90 (1H, dd), 6.91 (1H, dd), 6.96- 7.03 (1H, m),7.03- 7.10 (1H, m), 7.23- 7.29 (1H, m), 7.46 512 (1H, d), 10.64 (1H, s).(Two hydrogen multiplet obscured by DMSO). 28

3-fluoro-N-(2- (2-fluoro-4- methoxy-5- ((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)phenoxy) ethyl)propan-1- amine ¹HNMR (300 MHz, DMSO-d₆, 27° C.) 1.09(3H, d), 1.51- 1.78 (3H, m), 2.41- 2.48 (2H, m), 2.54- 2.69 (3H, m),2.77- 3.05 (2H, m), 3.33- 3.55 (2H, m), 3.63- 3.81 (2H, m), 3.84 (3H,s), 4.39 (2H, dt), 5.32 (1H, s), 6.44 (1H, d), 6.92-7.00 (1H, m),7.00-7.06 (1H, m), 7.07 (1H, d), 7.19-7.26 (1H, 512 m), 7.44 (1H, d),10.47 (1H, s). 29

N-(2-(2,5- difluoro-4- methoxy-3- ((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)phenoxy) ethyl)-3- fluoropropan- 1-amine ¹H NMR (500 MHz, CDCl₃, 27°C.) 1.18 (3H, d), 1.84 (2H, dddd), 2.64 (1H, ddd), 2.76 (2H, t), 2.95(2H, dd), 2.97- 3.05 (1H, m), 3.11 (1H, ddd), 3.25 (1H, dq), 3.60-3.68(1H, m), 3.69 (3H, d), 4.01 (2H, td), 4.44 (1H, t), 4.54 (1H, t), 5.40(1H, s), 6.76 (1H, dd), 7.05-7.14 (2H, m), 7.18-7.22 530 (1H, m),7.49-7.52 (1H, m), 7.63 (1H, s). (1 exchangeable not observed) 30

N-(2-(3,4- difluoro-5- ((1R,3R)-3- methyl-2- (2,2,2- trifluoroethyl)-2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1- yl)phenoxy) ethyl)-3-fluoropropan- 1-amine ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.17 (3H, d), 1.82(2H, dddd), 2.58 (1H, ddd), 2.72 (2H, t), 2.87 (2H, t), 2.88- 3.01 (2H,m), 3.25 (1H, dd), 3.42-3.53 (1H, m), 3.83 (2H, t), 4.41 (1H, t), 4.51(1H, t), 5.29 (1H, s), 6.30 (1H, dt), 6.64 (1H, ddd), 7.12 (1H, td),7.14-7.21 (1H, m), 7.25 (1H, dd), 500 7.49-7.58 (1H, m), 7.87 (1H, s).(1 exchangeable not observed) 31

N-(2-(2,5- difluoro-3- ((1R,3R)-3- methyl-2- (2,2,2- trifluoroethyl)-2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1- yl)phenoxy) ethyl)-3-fluoropropan- 1-amine ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.19 (3H, d), 1.92(2H, dddd), 2.59 (1H, ddd), 2.85 (2H, t), 2.91 (1H, dd), 2.96 (1H, dd),3.06 (2H, td), 3.27 (1H, dq), 3.47-3.52 (1H, m), 4.11 (2H, td), 4.51(1H, t), 4.60 (1H, t), 5.31 (1H, s), 6.32 (1H, ddd), 6.62 (1H, dd), 7.12(1H, td), 7.15-7.20 (1H, m), 500 7.25-7.30 (1H, m), 7.53 (1H, d), 7.88(1H, s). (1 exchangeable not observed) 32

3-fluoro-N-(2- (2,4,5- trifluoro-3- ((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)phenoxy) ethyl)propan-1- amine ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.18(3H, d), 1.86 (2H, dddd), 2.65 (1H, ddd), 2.79 (2H, t), 2.86-3.02 (3H,m), 3.08 (1H, ddd), 3.29 (1H, dq), 3.59 (1H, d), 4.01-4.11 (2H, m), 4.47(1H, t), 4.56 (1H, t), 5.38 (1H, s), 6.83 (1H, dt), 7.11 (1H, td),7.13-7.19 (1H, m), 7.21-7.25 (1H, m), 7.49-7.54 518 (1H, m), 7.55 (1H,s). (1 exchangeable not observed). 33

3-fluoro-N-(2- (4-fluoro-2- methyl-3- ((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)phenoxy) ethyl)propan-1- amine ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.17(3H, d), 1.74-1.96 (5H, m), 2.66-2.81 (3H, m), 2.85-3.04 (3H, m),3.13-3.31 (2H, m), 3.66-3.77 (1H, m), 3.98 (2H, ddt), 4.43 (1H, t), 4.52(1H, t), 5.46 (1H, s), 6.82 (1H, dd), 6.92 (1H, t), 7.06-7.15 (2H, m),7.16-7.23 (1H, m), 7.38 (1H, s), 7.46- 496 7.56 (1H, m). (1 exchangeablenot observed). 34

3-fluoro-N-(2- ((6-((1S,3R)-3- methyl-2- (2,2,2- trifluoroethyl)-2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1- yl)pyridin-2-yl)oxy)ethyl) propan-1-amine ¹H NMR (500 MHz, DMSO-d₆, 27° C.) 1.19 (3H,d), 1.62- 1.78 (2H, m), 2.52- 2.62 (3H, m), 2.63- 2.67 (1H, m), 2.72-2.83 (2H, m), 3.00- 3.13 (1H, m), 3.25- 3.35 (2H, m), 3.54- 3.69 (1H,m), 4.21- 4.32 (2H, m), 4.46 (2H, dt), 4.96 (1H, s), 6.67 (1H, d), 6.92-6.96 (1H, m), 7.00 (1H, d), 7.03-7.08 465 (1H, m), 7.30 (1H, d), 7.41(1H, d), 7.67 (1H, t), 10.67 (1H, s) 35

3-fluoro-N-(2- ((2-((1S,3R)-3- methyl-2- (2,2,2- trifluoroethyl)-2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1- yl)pyridin-4-yl)oxy)ethyl) propan-1-amine ¹H NMR (500 MHz, DMSO-d₆, 27° C.) 1.18 (3H,d), 1.69- 1.81 (2H, m), 1.86 (1H, br s), 2.54- 2.66 (4H, m), 2.86 (2H,t), 2.99-3.11 (1H, m), 3.23-3.30 (1H, m), 3.57-3.67 (1H, m), 4.05 (2H,br t), 4.47 (2H, dt), 4.99 (1H, s), 6.90 (1H, dd), 6.92-6.96 (1H, m),6.98 (1H, br d), 7.00-7.04 (1H, m), 465 7.30 (1H, d), 7.40 (1H, d), 8.33(1H, d), 10.67 (1H, s) 36

3-fluoro-N-(2- ((6-methoxy-5- ((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)pyridin-3- yl)oxy)ethyl) propan-1-amine ¹H NMR (300 MHz, DMSO-d₆, 27°C.) 1.09 (3H, d), 1.62- 1.77 (3H, m), 2.52- 2.64 (3H, m), 2.70- 2.80(3H, m), 2.99 (1H, br dq) 3.14- 3.28 (1H, m) 3.51 (1H, dq), 3.87 (2H,t), 3.91 (3H, s), 4.41 (2H, dt), 5.26 (1H, s), 6.52 (1H, d), 6.94- 7.02(1H, m), 7.02- 7.09 (1H, m), 7.21- 7.26 (1H, m), 7.46 495 (1H, d), 7.81(1H, d), 10.59 (1H, s). 37

3-fluoro-N-(2- ((6-methyl-5- ((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)pyridin-3- yl)oxy)ethyl) propan-1-amine ¹H NMR (500 MHz, CDCl₃, 27°C.) 1.15 (3H, d), 1.74-1.91 (2H, m), 2.60-2.69 (4H, m), 2.73 (2H, t),2.85-3.00 (4H, m), 3.23 (1H, dq), 3.37- 3.44 (1H, m), 3.89 (2H, tt),4.43 (1H, t), 4.52 (1H, t), 5.06 (1H, s), 6.70 (1H, d), 7.11-7.21 (2H,m), 7.29 (1H, d), 7.55 (1H, d), 7.92 (1H, d), 8.57 (1H, s). (1 479exchangeable not observed). 38

3-fluoro-N-(2- ((4-methyl-5- ((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)pyridin-3- yl)oxy)ethyl) propan-1-amine ¹H NMR (500 MHz, CDCl₃, 27°C.) 1.16 (3H, d), 1.87 (1H, ddd), 1.92 (1H, ddd), 2.19 (3H, s), 2.63-2.71 (1H, m), 2.84 (2H, t), 2.95-3.08 (4H, m), 3.20 (1H, dt), 3.48-3.57(1H, m), 4.10-4.22 (2H, m), 4.49 (1H, t), 4.58 (1H, t), 5.05 (1H, s),7.10-7.19 (2H, m), 7.23-7.25 (1H, m), 7.53 (2H, d), 7.84 479 (1H, s),8.17 (1H, s). (1 exchangeable not observed). 39

3-fluoroN-(2- ((5-fluoro-4- ((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)pyridin-2- yl)oxy)ethyl) propan-1-amine ¹H NMR (500 MHz, CDCl₃, 27°C.) 1.20 (3H, d), 1.83 (2H, dddd), 2.54 (1H, ddd), 2.66-2.80 (3H, m),2.83-2.99 (3H, m), 3.19-3.36 (2H, m), 4.27 (2H, td), 4.42 (1H, t), 4.52(1H, t), 5.25 (1H, s), 6.25 (1H, d), 7.14 (1H, ddd), 7.19 (1H, ddd),7.28 (1H, dt), 7.54 (1H, d), 7.98 (1H, d), 8.13 (1H, s). 483 (1exchangeable not observed) 40

N1-(3- fluoropropyl)- N2-(4- methoxy-3- ((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)phenyl) ethane-1,2- diamine ¹HNMR (300 MHz, DMSO-d₆, 27° C.) 1.09(3H, d), 1.61- 1.74 (3H, m), 2.44- 2.49 (m, 2 H), 2.53- 2.64 (2H, m),2.71- 3.01 (4H, m), 3.34- 3.44 (2H, m), 3.76 (3H, s), 4.42 (2H, dt),4.96 (1H, t), 5.34 (1H, s), 6.03 (1H, d) 6.45 (1H, dd), 6.86 (1H, d),6.93-6.99 (1H, m), 6.99-7.06 (1H, m), 7.18-7.26 493 (1H, m), 7.43 (1H,d), 10.52 (1H, d). (One hydrogen not observed, obscured by DMSO) 41

N1-(3- fluoropropyl)- N2-(6- methoxy-5- ((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)pyridin-3- yl)ethane-1,2- diamine ¹H NMR (300 MHz, DMSO-d₆, 27° C.)1.09 (3H, d), 1.58- 1.78 (3H, m), 2.54- 2.64 (3H, m), 2.70- 2.78 (1H,m), 2.85- 3.04 (3H, m), 3.24- 3.35 (1H, obsc m), 3.41-3.57 (1H, m), 3.84(3H, s), 4.43 (2H, dt), 5.10 (1H, t), 5.24 (1H, s), 6.43 (1H, d),6.91-6.99 (1H, m), 6.99-7.06 (1H, m), 7.18-7.27 494 (1H, m), 7.38 (1H,d), 7.45 (1H, d), 10.58 (1H, s). (Two hydrogen not observed, obscured byDMSO) 42

N1-( 3- fluoropropyl)- N2-(5- methoxy-4- (1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)pyridin-2- yl)ethane-1,2- diamine ¹H NMR (300 MHz, DMSO-d₆, 27° C.)1.11 (3H, d), 1.58 (1H, br d), 1.60- 1.82 (2H, m), 2.52- 2.74 (6H, m),2.84- 3.05 (1H, m), 3.07- 3.21 (2H, m), 3.26- 3.39 (1H, obsc m), 3.49(1H, dq), 3.81 (3H, s), 4.44 (2H, dt), 5.25 (1H, s), 5.83 (1H, s), 6.00(1H, t), 6.95-7.01 (1H, m), 7.01-7.09 (1H, m), 494 7.22-7.28 (1H, m),7.45 (1H, d), 7.79 (1H, s), 10.61 (s, 1 H). 43

N1-(3- fluoropropyl)- N2-(5- methoxy-6- ((1S,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)pyridin-2- yl)ethane-1,2- diamine ¹HNMR (300 MHz, DMSO-d₆, 27° C.)1.15 (3H, d), 1.23- 1.42 (1H, m), 1.55- 1.68 (2H, m), 2.35- 2.44 (4H,m), 2.52- 2.58 (1H, m), 2.65 (1H, dd), 2.89-3.07 (3H, m), 3.48 (1H, dq),3.77 (3H, s), 4.08-4.20 (1H, m), 4.40 (2H, dt), 5.40 (1H, s), 5.86(1H,t), 6.40 (1H, d), 6.92- 7.03 (2H, m), 7.18- 494 7.25 (1H, m), 7.30(1H, d), 7.39 (1H, d), 10.32 (1H, s). 44

3-((1R,3R)-1- (2-chloro-5-(2- ((3- fluoropropyl) amino)ethoxy)phenyl)-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4- b]indol-2-yl)-2,2- difluoropropan- 1-ol 1H NMR (500 MHz, CDCl3, 27° C.) 1.18 (3H, d),1.78-1.89 (2H, m), 2.69 (1H, ddd), 2.74 (2H, t), 2.78-2.87 (1H, m), 2.89(2H, ddd), 3.12- 3.26 (2H, m), 3.60 (1H, ddd), 3.66- 3.74 (1H, m), 3.74-3.81 (1H, m), 3.88- 3.98 (2H, m), 4.44 (1H, t), 4.53 (1H, t), 5.34 (1H,s), 6.79- 6.87 (2H, m), 7.09- 510 7.17 (2H, m), 7.22 (1H, dt), 7.35 (1H,d), 7.42 (1H, s), 7.51- 7.57 (1H, m). (2 exchangeables not observed). 45

2,2-difluoro-3- ((1R,3R)-1-(6- fluoro-3-(2- ((3- fluoropropyl)amino)ethoxy)- 2- methylphenyl)- 3-methyl- 1,3,4,9- tetrahydro-2H-pyrido[3,4- b]indol-2- yl)propan-1-ol ¹H NMR (500 MHz, CDCl₃, 27° C.)1.18 (3H, d), 1.78-2.00 (5H, m), 2.70-2.89 (4H, m), 2.98 (2H, tq),3.13-3.24 (2H, m), 3.53-3.64 (2H, m), 3.75-3.85 (1H, m), 4.02 (2H, t),4.46 (1H, t), 4.55 (1H, t), 5.34 (1H, s), 6.84 (1H, dd), 6.94 (1H, t),7.07-7.15 (2H, m), 7.17-7.23 (1H, m), 7.29 (1H, s), 7.50 508 (1H, dd).(2 exchangeables not observed). 46

2,2-difluoro-3- ((1R,3R)-6- fluoro-1-(5-(2- ((3- fluoropropyl)amino)ethoxy)- 2- methoxyphenyl)- 3-methyl- 1,3,4,9- tetrahydro-2H-pyrido[3,4- b]indol-2- yl)propan-1-ol ¹H NMR (500 MHz, CDCl₃, 27° C.)1.20 (3H, d), 1.79-1.91 (2H, m), 2.59 (1H, ddd), 2.75 (2H, t), 2.84-3.01(4H, m), 3.12-3.23 (1H, m), 3.63-3.73 (2H, m), 3.78 (1H, q), 3.86- 3.97(5H, m), 4.44 (1H, t), 4.54 (1H, t), 5.34 (1H, s), 6.64 (1H, d),6.81-6.92 (3H, m), 7.10-7.17 (2H, m), 7.67 (1H, s). (2 exchangeables notobserved). 524 47

2,2-difluoro-3- ((1R,3R)-1-(5- (((R)-1-((3- fluoropropyl) amino)propan-2-yl)oxy)-2- methoxyphenyl)- 3-methyl- 1,3,4,9- tetrahydro-2H-pyrido[3,4- b]indol-2- yl)propan-1-ol ¹H NMR (DMSO-d6, 300 MHz) 1.00-1.13 (6H, m), 1.52- 1.70 (2H, m), 2.38- 2.46 (4H, m), 2.53- 2.79 (4H,m), 2.98- 3.17 (1H, m), 3.65- 3.82 (5H, m), 4.06- 4.19 (1H, m), 4.31(1H, t), 4.47 (1H, t), 5.21 (1H, br s), 5.35 (1H, s), 6.11 (1H, d), 6.86(1H, dd), 6.91- 7.08 (3H, m), 7.21 (1H, d), 7.44 (1H, d), 520 10.56 (1H,s). (NH not observed) 48

2,2-difluoro-3- ((1R,3R)-1-(5- (((S)-1-((3- fluoropropyl) amino)propan-2-yl)oxy)-2- methoxyphenyl)- 3-methyl- 1,3,4,9- tetrahydro-2H-pyrido[3,4- b]indol-2- yl)propan-1-ol ¹H NMR (DMSO-d6, 400 MHz) 1.05-1.08 (6H, m), 1.59- 1.69 (2H, m), 2.42- 2.51 (4H, m), 2.52- 2.77 (4H,m), 3.03- 3.20 (1H, m), 3.68- 3.91 (5H, m), 4.11- 4.24 (1H, m), 4.34(1H, t), 4.46 (1H, t), 5.23 (1H, t), 5.36 (1H, s), 6.12 (1H, d), 6.86(1H, dd), 6.93- 7.08 (3H, m), 7.22 (1H, d), 7.45 (1H, d), 520 10.58 (1H,s). (NH not observed) 49

2,2-difluoro-3- ((1R,3R)-1-(5- ((S)-2-((3- fluoropropyl) amino)propoxy)-2- methoxyphenyl)- 3-methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2- yl)propan-1-ol 1H NMR (Methanol- d4, 300 MHz) 1.16 (3H, d),1.31 (3H, d), 1.83-2.08 (2H, m), 2.63 (1H, dd), 2.73- 2.91 (2H, m),2.94- 3.31 (3H, m), 3.40- 3.58 (2H, m), 3.69- 3.98 (6H, m), 4.04 (1H,dd), 4.39 (1H, t), 4.55 (1H, t), 5.49 (1H, s), 6.47 (1H, d), 6.93 (1H,dd), 6.98- 7.12 (3H, m), 7.24 (1H, d), 7.47 (1H, d), 8.54 (1H, s). (NHand OH not observed) 520 50

2,2-difIuoro-3- ((1R,3R)-1-(5- ((S)-2-((3- fluoropropyl) amino)propoxy)-2- methoxyphenyl)- 3-methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2- yl)propan-1-ol 1H NMR (Methanol- d4, 300 MHz) 1.16 (3H, d),1.31 (3H, d), 1.86-2.10 (2H, m), 2.63 (1H, dd), 2.68- 2.91 (2H, m),2.97- 3.32 (3H, m), 3.39- 3.57 (2H, m), 3.70- 3.96 (6H, m), 4.05 (1H,dd), 4.39 (1H, t), 4.55 (1H, t), 5.49 (1H, s), 6.47 (1H, d), 6.93 (1H,dd), 6.99- 7.12 (3H, m), 7.25 (1H, d), 7.47 (1H, d), 8.53 (1H, s). (NHand OH not observed) 520 51

N-(2-(3- ((1R,3R)-2- (2,2- difluoroethyl)- 3-methyl- 2,3,4,9-tetrahydro-1H- pyrido[3,4- b]indol-1-yl)- 2,4- difluorophenoxy)ethyl)-3- fluoropropan- 1-amine ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.17(3H, d), 1.82-1.94 (2H, m), 2.64 (1H, ddd), 2.72-2.83 (3H, m), 2.97-3.00(2H, m), 3.02-3.12 (2H, m), 3.48-3.56 (1H, m), 4.06-4.11 (2H, m), 4.52(2H, dt), 5.30 (1H, s), 5.67 (1H, tdd), 6.80 (1H, td), 6.92 (1H, td),7.08-7.15 (2H, m), 7.22-7.25 (1H, m), 7.50-7.54 (2H, m). 482 (1exchangeable not observed). 52

3-fluoro-N-(2- (3-((1R,3R)-2- ((1- fluorocyclopropyl) methyl)-3- methyl-2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)- 4- methoxyphenoxy)ethyl)propan- 1-amine ¹HNMR (300 MHz, DMSO-d₆, 27° C.) 0.55-0.68 (2H,m), 0.90-1.02 (2H, m), 1.05 (3H, dd), 1.56- 1.76 (2H, m), 1.84 (1H, brs), 2.52- 2.64 (4H, m), 2.67- 2.78 (2H, m), 2.85 (1H, dd), 3.06 (1H,dd), 3.47-3.60 (1H, m), 3.78-3.81 (2H, m), 3.85 (3H, s), 4.42 (2H, dt),5.35 (1H, s), 6.38 (1H, d), 6.83 484 (1H, dd), 6.88-7.08 (3H, m), 7.21(1H, dd), 7.42 (1H, d), 10.27 (1H, s). 53

(S)-3-((1R,3R)- 1-(5-(2-((3- fluoropropyl) amino)ethoxy)- 2-methoxyphenyl)- 3-methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2-yl)- 2- methylpropanoic acid ¹H NMR (500 MHz, CDCl₃, 27° C.)1.13 (3H, d), 1.25 (3H, d), 1.72-1.89 (2H, m), 2.57-2.69 (2H, m), 2.71(2H, t), 2.80- 2.88 (4H, m), 2.97 (1H, s), 3.56 (1H, ddd), 3.80 (3H, s),3.87 (2H, t), 4.42 (1H, t), 4.51 (1H, t), 5.59 (1H, s), 6.35 (1H, s),6.82 (1H, dd), 6.85 (1H, d), 7.17 (1H, td), 7.19- 498 7.24 (1H, m),7.27- 7.36 (1H, m), 7.56 (1H, d), 7.89 (1H, s). (2 exchangeables notobserved) 54

(S)-3-((1R,3R)- 1-(6-chloro-2- fluoro-3-(2- ((3- fluoropropyl)amino)ethoxy) phenyl)-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2-yl)- 2- methylpropanoic acid ¹H NMR (500 MHz, CDCl₃, 27° C.)1.01 (3H, d), 1.28 (3H, d), 1.85 (2H, dq), 2.14 (1H, br s), 2.69- 2.86(4H, m), 2.88- 3.03 (3H, m), 3.15 (1H, d), 3.66 (1H, q), 4.01-4.09 (2H,m), 4.43 (1H, t), 4.52 (1H, t), 5.62 (1H, s), 6.93 (1H, t), 7.10- 7.18(3H, m), 7.24 (1H, d), 7.50-7.56 (1H, m), 7.73 (1H, 520 s). (2exchangeables not observed) 55

(S)-3-((1R,3R)- 1-(6-fluoro-3- (2-((3- fluoropropyl) amino)ethoxy)- 2-methylphenyl)- 3-methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2-yl)- 2- methylpropanoic acid ¹H NMR (500 MHz, CDCl₃, 27° C.)0.86 (3H, d), 1.20 (3H, d), 1.82-1.97 (5H, m), 2.68-2.80 (3H, m), 2.83(3H, t), 2.94- 3.07 (2H, m), 3.21 (1H, dd), 3.42 (2H, s), 3.54-3.65 (1H,m), 4.02 (1H, q), 4.40 (1H, t), 4.50 (1H, t), 5.47 (1H, s), 6.18 (1H,s), 6.77 (1H, dd), 6.89 (1H, t), 7.09 (2H, td), 7.14- 500 7.22 (1H, m),7.48- 7.52 (1H, m), 7.82 (1H, s). 56

3-fluoro-N-(2- ((5-methoxy-6- ((1S,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)pyridin-2- yl)oxy)ethyl) propan-1-amine ¹H NMR (300 MHz, DMSO-d₆, 27°C.) 1.15 (3H, d), 1.55- 1.68 (2H, m), 2.38 (2H, t), 2.54-2.61 (3H, m),2.64-2.73 (1H, m), 2.98-3.11 (1H, m), 3.43-3.56 (1H, m), 3.85 (3H, s),3.88 (2H, dt), 3.92- 4.00 (1H, m), 4.39 (2H, dt), 5.45 (1H, s), 6.72(1H, d), 6.92- 7.00 (2H, m), 7.18- 7.25 (1H, m), 7.38- 495 7.44 (1H, d),7.55 (1H, d), 10.37 (1H, s). (1 exchangeable not observed.) 58

(S)-3-((1R,3R)- 1-(2,6- difluoro-3-(2- ((3- fluoropropyl) amino)ethoxy)phenyl)-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4- b]indol-2-yl)- 2-methylpropano ic acid ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.06 (3H, d), 1.28(3H, d), 1.76-1.89 (2H, m), 2.51 (1H, s), 2.65- 2.79 (4H, m), 2.85 (1H,t), 2.91-3.02 (3H, m), 3.59-3.68 (1H, m), 4.04 (2H, t), 4.47 (2H, dt),5.45 (1H, s), 6.76 (1H, t), 6.87-6.94 (1H, m), 7.13 (2H, dtd), 7.26 (1H,d), 7.52 (1H, d), 8.26 (1H, s). (2 exchangeables not observed.) 504 59

(S)-3-((1R,3R)- 1-(2,6- difluoro-3-(2- ((3- fluoropropyl) amino)ethoxy)phenyl)-6- fluoro-3- methyl- 1,3,4,9- tetrahydro-2H- ¹H NMR (500 MHz,CDCl₃, 27° C.) 1.06 (3H, d), 1.29 (3H, d), 1.77-1.91 (2H, m), 2.65 (1H,dd), 2.71- 3.01 (8H, m), 3.58- 3.67 (1H, m), 4.04 (2H, t), 4.47 (2H,dt), 5.44 (1H, s), 6.72- 6.79 (1H, m), 6.86- 6.95 (2H, m), 7.13- 522pyrido[3,4- 7.2 (2H, m), 8.45 b]indol-2-yl)- (1H, s). (2 2-exchangeables not methylpropanoic observed.) acid 60

3-((1R,3R)-1- (2,6-difluoro- 3-(2-((3- fluoropropyl) amino)ethoxy)phenyl)-8- fluoro-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2-yl)- 2,2- difluoropropan-1- ol ¹H NMR (300 MHz, DMSO-d₆, 27°C.) 1.10 (3H, d), 1.67- 1.85 (3H, m), 2.55- 2.71 (4H, m), 2.79- 2.89(3H, m), 3.17 (1H, q), 3.34-3.53 (2H, m), 3.56-3.76 (1H, m), 4.02 (2H,t), 4.47 (2H, dt), 5.24- 5.32 (2H, m), 6.81- 6.98 (3H, m), 7.16 (1H, brtd), 7.25 (1H, d), 11.13 (1H, s). 530 61

3-((1R,3R)-1- (2,6-difluoro- 3-(2-((3- fluoropropyl) amino)ethoxy)phenyl)-7- fluoro-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2-yl)- 2,2- difluoropropan-1- ol ¹H NMR (300 MHz, DMSO-d₆, 27°C.) 1.08 (3H, d), 1.67- 1.88 (3H, m), 2.53- 2.68 (4H, m), 2.80- 2.89(3H, m), 3.16 (1H, q), 3.37-3.51 (2H, m), 3.55-3.74 (1H, m), 4.02 (2H,t), 4.48 (2H, dt), 5.23 (1H, s), 5.26 (1H, t), 6.81 (1H, ddd), 6.91-7.00 (2H, m), 7.17 (1H, td), 7.39 (1H, dd), 10.71 (1H, s). 530 62

3-((1R,3R)-1- (2,6-difluoro- 3-(2-((3- fluoropropyl) amino)ethoxy)phenyl)-5- fluoro-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2-yl)- 2,2- difluoropropan-1- ol ¹H NMR (300 MHz, DMSO-d₆, 27°C.) 1.09 (3H, d), 1.64- 1.84 (2H, m), 1.79 (1H, s), 2.55-2.77 (4H, m),2.83 (2H, t), 2.99 (1H, dd), 3.16 (1H, q), 3.33-3.51 (2H, m), 3.64 (1H,br dd), 4.01 (2H, t), 4.46 (2H, dt), 5.21- 5.28 (2H, m), 6.68 (1H, ddd),6.90- 7.04 (3H, m), 7.16 (1H, td), 10.91 (1H, d). 530 63

3-((1R,3R)-1- (2,6-difluoro- 3-(2-((3- fluoropropyl) amino)ethoxy)phenyl)-3,6- dimethyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2-yl)- 2,2- difluoropropan-1- ol ¹HNMR (300 MHz, DMSO-d₆, 27°C.) 1.08 (3H, d), 1.66- 1.86 (3H, m), 2.36 (3H, s), 2.54-2.68 (4H, m),2.79-2.88 (3H, m), 3.06-3.24 (1H, m), 3.36-3.51 (2H, m), 3.56-3.74 (1H,m), 4.02 (2H, t), 4.47 (2H, dt), 5.22 (1H, br s), 5.26 (1H, t), 6.83(1H, dd), 6.90-6.97 (1H, m), 7.07 (1H, d), 7.11- 7.21 (2H, m), 10.43(1H, s). 526 64

3-((1R,3R)-1- (3,5-difluoro- 2-(2-((3- fluoropropyl) amino)ethoxy)pyridin-4-yl)-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2-yl)- 2,2- difluoropropan-1- ol ¹H NMR (500 MHz, CDCl₃, 27° C.)1.19 (3H, d), 1.80-1.94 (2H, m), 2.67 (1H, ddd), 2.80 (2H, t), 2.82-2.90(1H, m), 2.96-3.09 (3H, m), 3.17-3.29 (1H, m), 3.64 (1H, h), 3.70- 3.87(2H, m), 4.41 (1H, ddd), 4.44- 4.53 (2H, m), 4.56 (1H, t), 5.34 (1H, s),7.12 (1H, td), 7.16 (1H, td), 7.24 (1H, 513 dd), 7.52 (1H, d), 7.63 (1H,s), 7.79 (1H, s). (2 exchangeables not observed.) 65

3-((1R,3R)-1- (3,5-difluoro- 2-(2-((3- fluoropropyl) amino)ethoxy)pyridin-4-yl)-6- fluoro-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2-yl)- 2,2- difluoropropan-1- ol ¹H NMR (500 MHz, CDCl₃, 27° C.)1.19 (3H, d), 1.82-1.94 (2H, m), 2.62 (1H, dd), 2.78-2.90 (3H, m),2.96-3.05 (3H, m), 3.18-3.30 (1H, m), 3.63 (1H, q), 3.71-3.85 (2H, m),4.42 (1H, ddd), 4.45- 4.60 (3H, m), 5.33 (1H, s), 6.90 (1H, td), 7.16(2H, dd), 7.57 (1H, s), 7.80 (1H, s). (2 exchangeables not observed.)531 66

3-((1R,3R)-1- (3,5-difluoro- 2-(2-((3- fluoropropyl) amino)ethoxy)pyridin-4-yl)- 3,6-dimethyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2-yl)- 2,2- difluoropropan-1- ol ¹H NMR (300 MHz, DMSO-d₆, 27°C.) 1.08 (3H, d), 1.70- 1.89 (2H, m), 2.35 (3H, s), 2.52-2.68 (2H, m),2.74 (2H, br s), 2.91-3.06 (2H, m), 3.09-3.24 (1H, m), 3.34-3.67 (5H,m), 4.31-4.39 (2H, m), 4.50 (2H, dt), 5.22-5.33 (2H, m), 6.84 (1H, dd),7.08 (1H, d), 7.20 (1H, s), 7.93 (1H, s), 10.48 (1H, s). 527 67

3-((1R,3R)-1- (3,5-difluoro- 2-(2-((3- fluoropropyl) (methyl)amino)ethoxy)pyridin- 4-yl)-6- fluoro-3- methyl- 1,3,4,9- tetrahydro-2H-pyrido[3,4- b]indol-2-yl)- 2,2- difluoropropan-1- ol ¹H NMR (300 MHz,DMSO-d₆, 27° C.) 1.08 (3H, d), 1.61- 1.87 (2H, m), 2.21 (3H, s),2.41-2.46 (2H, m), 2.53-2.64 (2H, m), 2.70 (2H, t), 2.84 (1H, dd), 3.04-3.26 (1H, m), 3.33- 3.71 (3H, m), 4.29- 4.45 (4H, m), 5.27 (2H, s), 6.85(1H, td), 7.05-7.31 (2H, m), 7.94 (1H, s), 10.75 (1H, s). 545 68

3-((1R,3R)-1- (2- (difluoromethyl)- 3-(2-((3- fluoropropyl)amino)ethoxy) phenyl)-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2-yl)- 2,2- difluoropropan-1- ol ¹H NMR (400 MHz, DMSO-d6) 1.04(3H, d), 1.03 (1H, d) 1.74- 1.84 (2H, m), 2.53- 2.64 (1H, m), 2.64- 2.74(3H, m), 2.82- 2.90 (3H, m), 3.14 (1H, q), 3.38-3.55 (1H, m), 3.55-3.76(2H, m), 4.08-(2H, t), 4.45 (1H, t), 4.57 (1H, t), 5.21 (1H, s), 5.36(1H, t), 6.51 (1H, s), 6.95-7.10 (2H, m), 7.24-7.31 526 (2H, m), 7.42(1H, d), 7.44-7.80 (1H, m), 10.41 (1H, s) (1 exchangeable proton notobserved.) 69

2-(2-((3- fluoropropyl) amino)ethoxy)- 6-((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)benzonitrile ¹H NMR (300 MHz, DMSO-d₆, 27° C.) 1.10 (3H, d), 1.69-1.91 (3H, m), 2.61- 2.72 (3H, m), 2.89- 3.06 (4H, m), 3.39- 3.61 (2H,m), 4.18 (2H, t), 4.51 (2H, dt), 5.17 (1H, s), 6.76 (1H, d), 6.94-7.08(2H, m), 7.18-7.24 (2H, m), 7.45 (1H, d), 7.52 (1H, t), 10.52 (1H, s).489 70

(4-(2-((3- fluoropropyl) amino)ethoxy)- 2-((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)phenyl) methanol 1H NMR (400 MHz MeOH-d4, 27° C.) 1.15 (3H, d), 1.77-1.95 (2H, m), 2.74 (2H, t), 2.82-2.95 (3H, m), 2.99-3.18 (2H, m), 3.23(2H, q), 3.94-4.07 (2H, m), 4.40 (1H, t), 4.52 (1H, t), 5.11 (1H, dd),5.29 (1H, dd), 6.49 (1H, d), 6.61 (1H, d), 6.94-7.07 (2H, m), 7.05-7.14(1H, m), 7.23-7.33 494 (2H, m), 7.58 (1H, ddd) (3 exchangeable protonnot observed.) 71

3-fluoro-N-(2- (4- (methoxymethyl)- 3-((1R,3R)- 3-methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)phenoxy) ethyl)propan-1- amine ¹H NMR (DMSO-d₆, 400 MHz, 27° C.) 1.07(3H, d), 1.62- 1.80 (2H, m), 2.55 (2H, t), 2.64 (1H, dd), 2.75 (2H, t),2.85 (1H, dd), 2.94- 3.11 (1H, m), 3.33 (3H, s), 3.35-3.51 (2H, m), 3.85(2H, t), 4.38 (1H, t), 4.45- 4.56 (2H, m), 4.70 (1H, d), 5.17 (1H, s),6.34 (1H, s), 6.88 (1H, dd), 6.94-7.09 508 (2H, m), 7.22-7.29 (1H, m),7.36 (1H, d), 7.45 (1H, d), 10.51 (1H, s) (1 exchangeable proton notobserved.) 72

3,3,3-trifluoro- N-(2-(4- methoxy-3- ((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)phenoxy) ethyl)propan-1- amine ¹H NMR (DMSO-d₆, 400 MHz, 27° C.) 1.08(3H, d), 2.23- 2.40 (2H, m), 2.53- 2.61 (2H, m), 2.62- 2.69 (2H, m),2.69- 2.81 (3H, m), 2.87- 3.03 (1H, m), 3.38- 3.53 (1H, m), 3.78 (2H,t), 3.82 (3H, s), 5.36 (1H, s), 6.15 (1H, d), 6.82-6.90 (1H, m),6.93-7.08 (3H, m), 7.22 (1H, d), 7.44 (1H, d), 530 10.57 (1H, s) (1exchangeable proton not observed.) 73

3-fluoro-N-(2- (3-fluoro-5- ((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)phenoxy) ethyl)propan-1- amine ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.16(3H, d), 1.84-1.87 (2H, m), 2.50-2.56 (1H, m), 2.73-2.85 (3H, m),2.89-3.04 (3H, m), 3.13-3.35 (2H, m), 3.98 (2H, t), 4.47 (1H, t), 4.56(1H, t), 4.90 (1H, s), 6.52 (1H, ddd), 6.63- 6.69 (2H, m), 7.11- 7.16(1H, m), 7.19 (1H, dd), 7.28-7.33 (1H, m), 7.53 (1H, 482 d), 7.86 (1H,d). (1 exchangeable proton not observed.) 74

3-fluoro-N-(2- (2-fluoro-5- ((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)phenoxy) ethyl)propan-1- amine ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.15(3H, d), 1.86-1.89 (2H, m), 2.54-2.58 (1H, m), 2.80 (2H, t), 2.85 (1H,dd), 2.91- 2.97 (1H, m), 2.97- 3.01 (2H, m), 3.18- 3.27 (1H, m), 3.30-3.36 (1H, m), 4.07 (2H, t), 4.48 (1H, t), 4.57 (1H, t), 4.90 (1H, s),6.74 (1H, ddd), 6.97 (1H, dd), 7.04 (1H, dd), 7.13 482 (1H, ddd), 7.19(1H, ddd), 7.27-7.32 (1H, m), 7.53 (1H, d), 7.66 (1H, s). (1exchangeable proton not observed.) 75

N-(2-(3- ((1R,3R)-1,3- dimethyl-2- (2,2,2- trifluoroethyl)- 2,3,4,9-tetrahydro-1H- pyrido[3,4- b]indol-1- yl)phenoxy) ethyl)-3-fluoropropan- 1-amine ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.15 (3H, d), 1.74(3H, s), 1.80-1.97 (2H, m), 2.48-2.67 (2H, m), 2.80 (2H, t), 2.97 (2H,dd), 3.06-3.25 (2H, m), 3.27-3.35 (1H, m), 4.01 (2H, t), 4.53 (2H, dt),6.72- 6.76 (1H, m), 6.91 (2H, br s), 7.12- 7.18 (2H, m), 7.22 (1H, ddd),7.39 (1H, dt), 7.49-7.53 (1H, 478 m), 7.98 (1H, s). (1 exchangeable notobserved.) 76

N-(2-(2,4- difluoro-3- ((1R,3R)-2-((1- fluorocyclopropyl) methyl)-3-methyl- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1- yl)phenoxy)ethyl)-3- fluoropropan- 1-amine ¹H NMR (500 MHz, CDCl₃, 27° C.) 0.43-0.55 (2H, m), 0.92- 1.04 (2H, m), 1.15 (3H, d), 1.81-1.94 (2H, m), 2.65(1H, ddd), 2.72 (1H, dd), 2.79 (2H, t), 2.98 (2H, dd), 3 .09 (1H, ddd),3.17 (1H, dd), 3.71-3.79 (1H, m), 4.03-4.09 (2H, m), 4.52 (2H, dt), 5.35(1H, s), 6.77 (1H, td), 6.89 (1H, td), 490 7.07-7.14 (2H, m), 7.20-7.23(1H, m), 7.45 (1H, s), 7.48- 7.55 (1H, m). (1 exchangeable notobserved.) 77

N-(2-(2,4- difluoro-3- ((1R,3R)-3- methyl-2-((1- (methylsulfonyl)cyclopropyl) methyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)phenoxy) ethyl)-3- fluoropropan- 1-amine ¹H NMR (500 MHz, CDCl₃, 27°C.) 0.56- 0.66 (1H, m), 0.87- 0.93 (1H, m), 1.11 (3H, d), 1.39-1.48 (2H,m), 1.80-1.94 (2H, m), 2.67-2.84 (4H, m), 2.98 (2H, s), 3.08-3.17 (4H,m), 3.18-3.28 (1H, m), 3.81-3.90 (1H, m), 4.09 (2H, d), 4.51 (2H, dt),5.14 (1H, s), 6.82 (1H, t), 6.92-6.99 (1H, m), 550 7.07-7.15 (2H, m),7.19-7.23 (1H, m), 7.47-7.53 (1H, m), 7.58 (1H, s). (1 exchangeable notobserved.) 78

N-(2-(4- chloro-2- fluoro-3- ((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)phenoxy) ethyl)-3- fluoropropan- 1-amine ¹H NMR (500 MHz, DMSO-d₆,27° C.) 1.12 (3H, d), 1.67- 1.84 (3H, m), 2.62 (2H, br t), 2.64-2.70(1H, m), 2.80-2.87 (2H, m), 2.87-2.98 (1H, m), 2.99-3.06 (1H, m),3.49-3.60 (2H, m), 4.00-4.07 (2H, m), 4.46 (2H, dt), 5.45 (1H, s), 6.93-6.98 (1H, m), 6.99- 7.03 (1H, m), 7.19 (1H, d), 7.21-7.30 516 (2H, m),7.41 (1H, d), 10.54 (1H, s). 79

N-(2-(2,4- dimethyl-3- ((1R,3R)-3- methyl-2- (2,2,2- trifluoroethyl)-2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1- yl)phenoxy) ethyl)-3-fluoropropan- 1-amine ¹H NMR (500 MHz, DMSO, 27° C.) 1.12 (3H, d),1.63-1.87 (6H, m), 2.36-2.45 (3H, m), 2.59 (1H, t), 2.64-2.82 (4H, m),2.93 (1H, t), 3.02- 3.11 (1H, m), 3.32- 3.43 (1H, m), 3.55- 3.65 (1H,m), 3.83- 4.07 (2H, m), 4.36- 4.59 (2H, m), 5.24- 5.40 (1H, m), 6.83(1H, s), 6.84-7.09 (3H, m), 7.16 (1H, t), 492 7.37 (1H, d), 10.05- 10.2(1H, m). (1 exchangeable not observed). 80

3-fluoro-N-(2- (2-fluoro-4- methyl-3- ((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)phenoxy) ethyl)propan-1- amine ¹H NMR (600 MHz, DMSO-d₆, 27° C.) 1.13(3H, d), 1.75- 1.91 (6H, m), 2.70 (3H, dd), 2.83 (1H, qd), 2.91 (2H, brt), 3.05 (1H, qdd), 3.48 (1H, br qd), 3.56- 3.65 (1H, m), 4.01- 4.13(2H, m), 4.52 (2H, td), 5.37 (1H, s), 6.84 (1H, br d), 6.95 (1H, ddd),7.00 (1H, ddd), 7.04 (1H, dd), 7.19 (1H, d), 496 7.41 (1H, d), 10.43(1H, s) 81

2,2-difluoro-3- ((1R,3R)-1-(2- fluoro-3-(2- ((3- fluoropropyl)amino)ethoxy)- 6- methoxyphenyl)- 3-methyl- 1,3,4,9- tetrahydro-2H-pyrido[3,4- b]indol-2- yl)propan-1-ol ¹H NMR (300 MHz, DMSO-d₆, 27° C.)1.06 (3H, d), 1.59- 1.82 (3H, m), 2.53- 2.68 (4H, m), 2.76 (2H, br t),2.85-2.96 (1H, m), 3.00-3.14 (1H, m), 3.22-3.39 (1H, m), 3.51 (1H, sxt),3.56-3.74 (1H, m), 3.78 (3H, s), 3.85- 3.99 (2H, m), 4.44 (2H, dt), 5.17(1H, t), 5.35 (1H, s), 6.81 (1H, dd), 6.95 (2H, 524 quind), 7.10 (1H,t), 7.15-7.20 (1H, m), 7.38 (1H, d), 10.40 (1H, s) 82

N-(2-(3- ((1R,3R)-2- (2,2- difluoroethyl)- 3-methyl- 2,3,4,9-tetrahydro-1H- pyrido[3,4- b]indol-1-yl)- 2-fluoro-4- methoxyphenoxy)ethyl)-3- fluoropropan- 1-amine ¹HNMR (300 MHz, DMSO-d₆, 27° C.) 1.09(3H, d), 1.61- 1.83 (3H, m), 2.54- 2.73 (4H, m), 2.76 (2H, t), 2.84 (1H,dd), 3.04 (1H, qd), 3.34-3.43 (1H, m), 3.81 (3H, s), 3.85- 3.98 (2H, m),4.43 (2H, dt), 5.33 (1H, s), 5.64-6.10 (1H, m), 6.83 (1H, dd), 6.90-7.03(2H, m), 7.10 (1H, t), 7.16- 494 7.22 (1H, m), 7.36- 7.42 (1H, m), 10.49(1H, s). 83

3-fluoro-N-(2- (2-fluoro-3- ((1R,3R)-2-((1- fluorocyclopropyl)methyl)-3- methyl- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)- 4-methoxyphenoxy) ethyl)propan- 1-amine ¹HNMR (300 MHz, DMSO-d₆, 27° C.)0.36-0.52 (2H, m), 0.78-0.95 (2H, m), 1.05 (3H, d), 1.62- 1.83 (3H, m),2.54- 2.71 (4H, m), 2.77 (2H, t), 2.92 (1H, br ddd), 3.06 (1H, dd),3.54-3.67 (1H, m), 3.78 (3H, s), 3.84- 4.01 (2H, m), 4.44 (2H, dt), 5.35(1H, s), 6.81 (1H, dd), 6.89-6.99 (2H, m), 502 7.09 (1H, t), 7.15- 7.18(1H, m), 7.35- 7.40 (1H, m), 10.34 (1H, s) 84

3-fluoro-N-(2- (2-fluoro-3- ((1R,3R)-2-((3- fluorooxetan- 3-yl)methyl)-3-methyl- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)- 4-methoxyphenoxy) ethyl)propan- 1-amine ¹H NMR (300 MHz, DMSO-d₆, 27° C.)1.07 (3H, d), 1.60- 1.81 (3H, m), 2.53- 2.62 (3H, m), 2.71- 2.90 (4H,m), 3.08- 3.29 (1H, m), 3.37- 3.49 (1H, m), 3.78 (3H, s), 3.86-3.99 (2H,m), 4.20 (1H, dd), 4.33-4.56 (5H, m), 5.36 (1H, s), 6.83 (1H, dd), 6.95(2H, quind), 7.10 (1H, t), 7.15-7.20 (1H, m), 518 7.36-7.42 (1H, m),10.42 (1H, s). 85

3-((1R,3R)-1- (2-chloro-6- fluoro-3-(2- ((3- fluoropropyl) amino)ethoxy)phenyl)-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4- b]indol-2-yl)-2,2- difluoropropan- 1-ol ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.16 (3H, d),1.85-1.97 (2H, m), 2.70 (1H, d), 2.74-2.84 (1H, m), 2.86 (2H, t), 2.98-3.07 (2H, m), 3.17 (1H, ddd), 3.26 (1H, dt), 3.55-3.66 (2H, m),3.76-3.86 (1H, m), 4.09 (2H, tt), 4.47 (1H, t), 4.56 (1H, t), 5.50 (1H,s), 6.85 (1H, dd), 6.91 (1H, t), 7.02-7.13 528 (1H, m), 7.14-7.20 (1H,m), 7.20-7.27 (1H, m), 7.48-7.52 (1H, m), 7.69 (1H, s). (2 exchangeablesnot observed). 86

2,2-difluoro-3- ((1R,3R)-6- fluoro-1-(2- fluoro-3-(2- ((3- fluoropropyl)amino)ethoxy)- 6- methoxyphenyl)- 3-methyl- 1,3,4,9- tetrahydro-2H-pyrido[3,4- b]indol-2- yl)propan-1-ol ¹H NMR (500 MHz, CDCl₃, 27° C.)1.16 (3H, d), 1.80-1.92 (2H, m), 2.58-2.65 (1H, m), 2.78 (2H, t),2.81-2.92 (1H, m), 2.95 (2H, t), 3.09 (1H, ddd), 3.18- 3.27 (1H, m),3.35- 3.55 (2H, m), 3.61- 3.81 (6H, m), 4.06 (2H, t), 4.50 (2H, dt),5.33 (1H, s), 6.64 (1H, dd), 6.83 (1H, td), 6.97 (1H, t), 7.08 (1H, dd),7.13 (1H, dd), 7.49 (1H, s). 542 87

3-((1R,3R)-1- (6-fluoro-3-(2- ((3- fluoropropyl) amino)ethoxy)- 2-methylphenyl)- 3-methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4- b]indol-2-yl)propanenitrile ¹H NMR (DMSO-d₆, 300 MHz, 27° C.) 1.04 (3H, d), 1.88-1.95 (5H, m), 2.32- 2.46 (1H, m), 2.52- 2.65 (2H, m), 2.65- 2.83 (2H,m), 2.83- 2.92 (2H, m), 3.05- 3.15 (3H, m), 3.63 (1H, s), 3.97-4.14 (2H,m), 4.41 (1H, t), 4.56 (1H, t), 5.26 (1H, s), 6.89-7.05 (3H, m),7.06-7.23 (2H, m), 7.42 (1H, 467 d), 10.34 (1H, s). (1 exchangeableproton not observed.) 88

N1-(2,4- difluoro-3- ((1R,3R)-3- methyl-2- (2,2,2- trifluoroethyl)-2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1- yl)phenyl)-N2- (3-fluoropropyl)et hane-1,2- diamine ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.18(3H, d), 1.80-1.85 (2H, m), 2.62-2.65 (1H, m), 2.72-2.77 (2H, m), 2.87(2H, t), 2.95-3.04 (1H, m), 3.08-3.21 (3H, m), 3.22-3.27 (1H, m),3.58-3.67 (1H, m), 4.46 (1H, t), 4.56 (1H, t), 5.35 (1H, s), 6.61-6.64(1H, m), 6.73-6.81 (1H, m), 7.07-7.15 (2H, m), 499 7.23 (2H, d), 7.44-7.54 (2H, m). (1 exchangeable proton not observed.) 89

3-((1R,3R)-1- (2,6-difluoro- 3-((2-((3- fluoropropyl) amino)ethyl)amino)phenyl)-6- fluoro-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2-yl)- 2,2- difluoropropan- 1-ol ¹H NMR (500 MHz, CDCl₃, 27° C.)1.16 (3H, d), 1.92-2.03 (2H, m), 2.55-2.64 (1H, m), 2.81-2.94 (5H, m),3.05 (1H, dd), 3.15-3.38 (4H, m), 3.54-3.64 (1H, m), 3.68-3.78 (2H, m),4.38-4.55 (3H, m), 5.23 (1H, s), 6.60 (1H, td), 6.74-6.85 (2H, m),7.08-7.16 (2H, m), 7.93 (1H, s). (1 exchangeable not observed.) 529 90

N1-(2-fluoro- 4-methoxy-3- ((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)phenyl)-N2- (3- fluoropropyl) ethane-1,2- diamine ¹H NMR (300 MHz,DMSO-d₆, 27° C.) 1.10 (3H, d), 1.62- 1.80 (3H, m), 2.53- 2.67 (5H, m),2.87- 3.05 (4H, m), 3.36- 3.52 (2H, m), 3.73 (3H, s), 4.44 (2H, dt),4.67-4.73 (1H, m), 5.40 (1H, s), 6.67 (1H, t), 6.76 (1H, d), 6.95 (2H,quint), 7.16-7.20 (1H, m), 7.36-7.40 (1H, m), 10.44 (1H, s). 511 91

N1-(2-fluoro- 4-methoxy-5- ((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)phenyl)-N2- (3- fluoropropyl) ethane-1,2- diamine ¹H NMR (300 MHz,DMSO-d₆, 27° C.) 1.09 (3H, d), 1.49- 1.70 (3H, m), 2.37 (2H, t),2.42-2.47 (2H, m), 2.54-3.02 (5H, m), 3.36-3.49 (2H, m), 3.78 (3H, s),4.39 (2H, dt), 4.69- 4.75 (1H, m), 5.31 (1H, s), 6.14 (1H, d), 6.91-7.05(3H, m), 7.20-7.24 (1H, m), 7.43 (1H, d), 10.44 (1H, s). 511 92

3-fluoro-N-(2- ((3-fluoro-2- ((1S,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)pyridin-4- yl)oxy)ethyl) propan-1-amine ¹H NMR (300 MHz, DMSO-d₆, 27°C.) 1.10 (3H, d), 1.70- 1.88 (2H, m), 1.88- 2.05 (1H, m), 2.53- 2.72(4H, m), 2.94 (2H, t), 2.97-3.15 (1H, m), 3.47-3.71 (2H, m), 4.19 (2H,quin), 4.51 (2H, dt), 5.37 (1H, s), 6.93- 7.00 (1H, m), 7.00- 7.06 (1H,m), 7.17- 7.26 (2H, m), 7.43 (1H, d), 8.07 (1H, d), 10.58 (1H, s). 48393

N-(2-((3- chloro-2- ((1S,3R)-3- methyl-2- (2,2,2- trifluoroethyl)-2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1- yl)pyridin-4-yl)oxy)ethyl)- 3- fluoropropan- 1-amine ¹H NMR (300 MHz, DMSO-d₆, 27°C.) 1.11 (3H, d), 1.68- 1.96 (3H, m), 2.60- 2.74 (3H, m), 2.80- 3.08(4H, m), 3.33- 3.39 (1H, m), 3.56 (1H, br dd), 4.29- 4.64 (4H, m), 5.38(1H, s), 6.42 (1H, d), 6.96-7.02 (1H, m), 7.03-7.10 (1H, m), 7.21-7.26(1H, m), 7.47 (1H, d), 7.93 (1H, d), 10.61 (1H, s). 517 94

N1-(3-fluoro- 2-((1S,3R)-3- methyl-2- (2,2,2- trifluoroethyl)- 2,3,4,9-tetrahydro-1H- pyrido[3,4- b]indol-1- yl)pyridin-4- yl)-N2-(3-fluoropropyl) ethane-1,2- diamine ¹H NMR (300 MHz, DMSO-d₆, 27° C.) 1.10(3H, d), 1.68- 1.94 (3H, m), 2.54- 2.76 (6H, m), 2.93- 3.15 (1H, m),3.21 (2H, q), 3.45-3.63 (1H, m), 3.67-3.79 (1H, m), 4.51 (2H, dt), 5.29(1H, s), 6.43 (1H, br td), 6.66 (1H, dd), 6.92-6.98 (1H, m), 6.98-7.05(1H, m), 7.18-7.24 (1H, m), 7.39-7.45 (1H, 482 m), 7.77 (1H, d), 10.57(1H, s). 95

N1-(3- fluoropropyl)- N2-(3-methyl- 2-((1S,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)pyridin-4- yl)ethane-1,2- diamine ¹H NMR (300 MHz, DMSO-d₆, 27° C.)1.08 (3H, d), 1.67- 1.85 (2H, m), 1.93 (3H, s), 2.57-2.76 (5H, m), 2.85(1H, dd), 2.95-3.12 (1H, m), 3.19 (2H, q), 3.35-3.51 (1H, m), 3.59-3.69(1H, m), 4.49 (2H, dt), 5.14 (1H, s), 5.61 (1H, br t), 6.50 (1H, d),6.96 (2H, quind), 7.17- 7.22 (1H, m), 7.38- 478 7.43 (1H, m), 7.93 (1H,d), 10.32 (1H, s). (Dialkyl NH not observed.) 96

2,2-difluoro-3- ((1S,3R)-1-(4- (2-((3- fluoropropyl) amino)ethoxy)- 3-methylpyridin- 2-yl)-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2- yl)propan-1-ol ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.18 (3H, d),1.85-1.96 (2H, m), 2.22 (3H, s), 2.68 (1H, d), 2.76- 2.89 (3H, m), 3.08(2H, t), 3.11-3.25 (2H, m), 3.58 (1H, q), 3.75-3.85 (2H, m), 4.14 (2H,t), 4.55 (2H, dt), 5.23 (1H, s), 6.74 (1H, d), 7.06- 7.12 (2H, m), 7.19(1H, dd), 7.45-7.55 (2H, m), 8.29 (1H, 491 d). (2 exchangeables notobserved.) 97

2,2-difluoro-3- ((1S,3R)-1-(3- fluoro-4-(2- ((3- fluoropropyl)amino)ethoxy) pyridin-2-yl)-3- methyl- 1,3,4,9- tetrahydro-2H-pyrido[3,4- b]indol-2- yl)propan-1-ol ¹H NMR (300 MHz, DMSO-d₆, 27° C.)1.07 (3H, d), 1.70- 1.96 (2H, m), 2.52- 2.72 (3H, m), 2.75 (2H, t), 3.02(2H, br t), 3.08-3.23 (1H, m), 3.51-3.80 (3H, m), 4.22 (2H, br t), 4.51(2H, dt), 5.33 (1H, t), 5.38 (1H, s), 6.91-6.98 (1H, m), 6.98-7.04 (1H,m), 7.15-7.23 (2H, m), 7.41 (1H, d), 8.07 (1H, d), 10.55 (1H, 495 s).(Amine NH not observed.) 98

N-(2-((2- ((1S,3R)-2- (2,2- difluoroethyl)- 3-methyl- 2,3,4,9-tetrahydro-1H- pyrido[3,4- b]indol-1-yl)- 3- fluoropyridin- 4-yl)oxy)ethyl)- 3- fluoropropan- ¹H NMR (300 MHz, DMSO-d₆, 27° C.) 1.09(3H, d), 1.70- 1.94 (3H, m), 2.53- 2.78 (5H, m), 2.94 (2H, t), 3.06-3.25(1H, m), 3.41-3.59 (1H, m), 4.19 (2H, t), 4.51 (2H, dt), 5.37 (1H, s),6.05 (1H, tt), 6.92-6.99 (1H, m), 6.99-7.07 (1H, m), 7.17-7.25 (2H, m),7.42 (1H, d), 8.07 (1H, d), 10.55 (1H, 465 1-amine s). 99

3-fluoro-N-(2- ((3-fluoro-2- ((1S,3R)-2-((1- fluorocyclopropyl)methyl)-3- methyl- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)pyridin-4- yl)oxy)ethyl) propan-1-amine ¹H NMR (300 MHz, DMSO-d₆, 27°C.) 0.55-0.78 (2H, m), 0.83-1.05 (2H, m), 1.08 (3H, d), 1.70- 1.89 (2H,m), 1.90- 2.07 (1H, m), 2.52- 2.75 (5H, m), 2.94 (2H, t), 3.08-3.22 (1H,m), 3.58-3.70 (1H, m), 4.19 (2H, t), 4.51 (2H, dt), 5.49 (1H, s),6.90-7.04 (2H, m), 7.16-7.22 (2H, m), 7.41 (1H, 473 d), 8.07 (1H, d),10.50 (1H, s). 100 

3-fluoro-N-(2- ((3-fluoro-2- ((1S,3R)-2-((3- fluorooxetan- 3-yl)methyl)-3-methyl- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1- yl)pyridin-4-yl)oxy)ethyl) propan-1-amine ¹H NMR (300 MHz, DMSO-d₆, 27° C.) 1.13 (3H,d), 1.71- 1.94 (3H, m), 2.53- 2.72 (4H, m), 2.83 (1H, dd), 2.93 (2H, t),3.20-3.37 (1H, m), 3.44-3.59 (1H, m), 4.18 (2H, t), 4.41- 4.70 (6H, m),5.43 (1H, s), 6.92-6.99 (1H, m), 6.99-7.05 (1H, m), 7.16-7.23 (2H, m),7.39-7.45 (1H, m), 8.05 (1H, d), 10.54 (1H, s). 489 101 

3-fluoro-N-(2- ((5-((1R,3R)-3- methyl-2- (2,2,2- trifluoroethyl)-2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1- yl)pyridin-3-yl)oxy)ethyl) propan-1-amine ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.17 (3H,d), 1.79-1.97 (2H, m), 2.54 (1H, dd), 2.75-2.88 (3H, m), 2.95-3.03 (3H,m), 3.20-3.36 (2H, m), 4.00-4.11 (2H, m), 4.48 (1H, t), 4.57 (1H, t),4.99 (1H, s), 7.12-7.17 (2H, m), 7.20 (1H, ddd), 7.30- 7.34 (1H, m),7.54 (1H, d), 7.92 (1H, s), 8.14 (1H, d), 8.22 465 (1H, d). (1exchangeable proton not observed.) 102 

3-fluoro-N-(2- ((4-((1R,3R)-3- methyl-2- (2,2,2- trifluoroethyl)-2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1- yl)pyridin-2-yl)oxy)ethyl) propan-1-amine ¹HNMR (500 MHz, CDCl₃, 27° C.) 1.18 (3H,d), 1.81-1.94 (2H, m), 2.54 (1H, dd), 2.71-2.82 (3H, m), 2.91-3.02 (3H,m), 3.16-3.23 (1H, m), 3.24-3.30 (1H, m), 4.33-4.42 (2H, m), 4.47 (1H,t), 4.56 (1H, t), 4.93 (1H, s), 6.48-6.62 (1H, m), 7.00 (1H, dd), 7.15(1H, ddd), 7.20- 7.25 (1H, m), 7.32- 7.36 (1H, m), 7.54 465 (1H, d),7.81 (1H, s), 8.09 (1H, dd). (1 exchangeable proton not observed.) 103 

2,2-difluoro-3- ((1R,3R)-1-(2- (2-((3- fluoropropyl) amino)ethoxy)- 3-methylpyridin- 4-yl)-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2- yl)propan-1-ol ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.17 (3H, d),1.85-1.97 (2H, m), 2.30 (3H, s), 2.67 (1H, dd), 2.75-2.88 (3H, m),2.98-3.08 (3H, m), 3.12-3.24 (1H, m), 3.57-3.66 (1H, m), 3.72 (2H, t),4.44 (2H, td), 4.55 (2H, dt), 5.08 (1H, s), 6.49 (1H, d), 7.11-7.19 (2H,m), 7.21-7.25 (1H, m), 7.54 (1H, 491 d), 7.66 (1H, s), 7.82 (1H, d). (2exchangeables not observed.) 104 

3-((1R,3R)-1- (3-chloro-2-(2- ((3- fluoropropyl) amino)ethoxy)pyridin-4-yl)-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2-yl)- 2,2- difluoropropan- 1-ol ¹H NMR (300 MHz, DMSO-d₆, 27°C.) 1.00 (3H, d), 1.64- 1.82 (3H, m), 2.48- 2.67 (4H, m), 2.78- 2.90(3H, m), 3.03- 3.17 (1H, m), 3.28- 3.37 (1H, m), 3.38- 3.71 (2H, m),4.31 (2H, td), 4.44 (2H, dt), 5.14-5.24 (1H, m), 5.27 (1H, s), 6.39 (1H,d), 6.88-6.94 (1H, m), 6.94-7.01 (1H, m), 7.14 (1H, d), 7.39 (1H, d),7.84 (1H, d), 10.47 (1H, s). 511 105 

3-fluoro-N-(2- ((5-methyl-6- ((1S,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)pyridin-2- yl)oxy)ethyl) propan-1-amine ¹H NMR (500 MHz, CDCl₃, 27°C.) 1.19 (3H, d), 1.79-1.91 (2H, m), 2.13 (3H, s), 2.64 (1H, ddd), 2.75(2H, t), 2.86- 2.91 (2H, m), 2.95- 3.05 (1H, m), 3.10 (1H, ddd), 3.15-3.25 (1H, m), 3.54- 3.66 (1H, m), 4.17- 4.24 (1H, m), 4.26- 4.32 (1H,m), 4.51 (2H, dt), 5.13 (1H, s), 6.63 (1H, d), 7.07- 7.15 (2H, m), 7.24479 (1H, dt), 7.36 (1H, d), 7.49-7.53 (1H, m), 7.87 (1H, s). (1exchangeable not observed.) 106 

3-fluoro-N-(2- ((3-methyl-4- ((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)pyridin-2- yl)oxy)ethyl) propan-1-amine ¹H NMR (500 MHz, CDCl₃, 27°C.) 1.14 (3H, d), 1.82-1.96 (2H, m), 2.28 (3H, s), 2.55-2.67 (1H, m),2.84 (2H, t), 2.93 (2H, ddt), 2.99-3.05 (2H, m), 3.13-3.28 (1H, m),3.37-3.43 (2H, m), 4.34-4.45 (2H, m), 4.47 (1H, t), 4.57 (1H, t), 5.08(1H, s), 6.38 (1H, d), 7.11 (1H, td), 7.15 (1H, td), 7.21-7.29 (1H, m),7.53 (1H, 479 d), 7.70 (1H, d), 8.44 (1H, s). 107 

N-(2-((3,5- difluoro-4- ((1R,3R)-3- methyl-2- (2,2,2- trifluoroethyl)-2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1- yl)pyridin-2-yl)oxy)ethyl)- 3- fluoropropan- 1-amine ¹H NMR (500 MHz, CDCl₃, 27° C.)1.20 (3H, d), 1.87 (2H, dddd), 2.65 (1H, ddd), 2.80 (2H, t), 2.95 (1H,dt), 2.99- 3.09 (3H, m), 3.31 (1H, dq), 3.55 (1H, h), 4.43 (2H, ddd),4.47 (1H, t), 4.56 (1H, t), 5.37 (1H, s), 7.12 (1H, ddd), 7.14- 7.19(1H, m), 7.24- 7.28 (1H, m), 7.50- 7.55 (1H, m), 7.67 (1H, s), 7.77 (1H,s). 501 (1 exchangeable not observed). 108 

N-(2-((3,5- difluoro-4- ((1R,3R)-2-((1- fluorocyclopropyl) methyl)-3-methyl- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1- yl)pyridin-2-yl)oxy)ethyl)- 3- fluoropropan- 1-amine ¹H NMR (300 MHz, DMSO-d₆, 27°C.) 0.45-0.59 (2H, m), 0.79-0.96 (2H, m), 1.01 (3H, d), 1.60- 1.78 (3H,m), 2.45- 2.69 (4H, m), 2.75- 2.85 (3H, m), 3.03 (1H, dd), 3.42-3.53(1H, m), 4.26 (2H, t), 4.40 (2H, dt), 5.26 (1H, s), 6.85-6.92 (1H, m),6.92-6.99 (1H, m), 7.11-7.16 (1H, m), 7.36 (1H, d), 7.88 (1H, s), 10.56(1H, s). 491 109 

N-(2-((3,5- difluoro-4- ((1R,3R)-6- fluoro-2-((1- fluorocyclopropyl)methyl)-3- methyl- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)pyridin-2- yl)oxy)ethyl)- 3- fluoropropan- 1-amine ¹H NMR (300 MHz,DMSO-d₆, 27° C.) 0.44-0.60 (2H, m), 0.78-0.95 (2H, m), 1.00 (3H, d),1.69 (3H, dsxt), 2.45- 2.69 (4H, m), 2.73- 2.84 (3H, m), 3.02 (1H, dd),3.39-3.53 (1H, m), 4.26 (2H, t), 4.40 (2H, dt), 5.26 (1H, s), 6.78 (1H,td), 7.08-7.16 (2H, m), 7.89 (1H, s), 10.68 (1H, s). 509 110 

2,2-difluoro-3- ((1R,3R)-1-(5- fluoro-2-(2- ((3- fluoropropyl)amino)ethoxy)- 3- methylpyridin- 4-yl)-3- methyl- 1,3,4,9-tetrahydro-2H- pyrido[3,4- b]indol-2- yl)propan-1-ol ¹H NMR (500 MHz,CDCl₃, 27° C.) 1.17 (3H, d), 1.84 (2H, dddd), 1.93 (3H, s), 2.66-2.76(2H, m), 2.77 (2H, t), 2.96 (2H, qdd), 3.11- 3.24 (2H, m), 3.51- 3.69(2H, m), 3.72- 3.82 (1H, m), 4.32 (1H, ddd), 4.38- 4.48 (2H, m), 4.54(1H, t), 5.33 (1H, s), 7.07-7.16 (2H, m), 7.18-7.24 (1H, m), 7.43 (1H,s), 7.48- 509 7.54 (1H, m), 7.88 (1H, s). (2 exchangeables notobserved). 111 

3-((1R,3R)-1- (3-chloro-5- fluoro-2-(2- ((3- fluoropropyl) amino)ethoxy)pyridin-4-yl)-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2-yl)- 2,2- difluoropropan- 1-ol ¹H NMR (500 MHz, CDCl₃, 27° C.)1.14 (3H, d), 1.78-1.95 (2H, m), 2.54 (1H, d), 2.66-2.73 (1H, m),2.72-2.79 (1H, m), 2.81 (2H, t), 2.92 (1H, s), 3.01 (2H, t), 3.16 (1H,ddd), 3.25 (1H, dt), 3.61-3.70 (1H, m), 3.71-3.80 (1H, m), 4.34-4.50(3H, m), 4.55 (1H, t), 5.49 (1H, s), 7.10 (2H, tdd), 7.18 (1H, dd), 7.51(1H, dd), 529 7.76-7.83 (1H, m), 7.95 (1H, s). (1 exchangeable notobserved) 112 

3-fluoro-N-(2- ((6-methoxy-5- ((1R,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)pyridazin-3- yl)oxy)ethyl) propan-1-amine ¹H NMR (500 MHz, CDCl₃, 27°C.) 1.23 (3H, d), 1.76-1.92 (2H, m), 2.56 (1H, dd), 2.67-2.84 (3H, m),2.95 (3H, pt), 3.15-3.40 (2H, m), 4.20 (3H, s), 4.31- 4.49 (3H, m), 4.52(1H, t), 5.18 (1H, s), 6.49 (1H, s), 7.13 (1H, td), 7.19 (1H, td),7.30-7.35 (1H, m), 7.52 (1H, d), 8.59 (1H, s). (1 exchangeable notobserved). 496 113 

3-fluoro-N-(2- ((6-((1S,3R)-3- methyl-2- (2,2,2- trifluoroethyl)-2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1- yl)pyrimidin- 4-yl)oxy)ethyl) propan-1-amine ¹H NMR (400 MHz, DMSO-d₆, 27° C.) 1.24 (3H,d), 1.68- 1.86 (2H, m), 1.95 (1H, s), 2.52-2.67 (4H, m), 2.87 (2H, t),3.02-3.27 (2H, m), 3.59-3.75 (1H, m), 4.30-4.47 (3H, m), 4.54 (1H, t),5.02 (1H, s), 6.88 (1H, s), 6.92-7.01 (1H, m), 7.02-7.11 (1H, m), 7.35(1H, d), 7.42 (1H, d), 8.76 (1H, d), 10.77 (1H, s). 466 114 

3-fluoro-N-(2- ((5-methyl-6- ((1S,3R)-3- methyl-2- (2,2,2-trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)pyrimidin- 4- yl)oxy)ethyl) propan-1-amine ¹H NMR (400 MHz, DMSO-d₆,27° C.) 1.11 (3H, d), 1.69- 1.87 (2H, m), 1.92- 2.15 (4H, m), 2.59- 2.71(3H, m), 2.75- 2.85 (1H, m), 2.90 (2H, t), 3.00-3.16 (1H, m), 3.47-3.69(2H, m), 4.33-4.48 (3H, m), 4.56 (1H, t), 5.21 (1H, s), 6.92- 7.07 (2H,m), 7.18- 7.26 (1H, m), 7.40- 7.47 (1H, m), 8.51 (1H, s), 10.50 (1H, s)480 115 

2,2-difluoro-3- ((1S,3R)-1-(6- (2-((3- fluoropropyl) amino)ethoxy)- 5-methylpyrimidin- 4-yl)-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2- yl)propan-1-ol ¹H NMR (400 MHz, DMSO-d₆, 27° C.) 1.10 (3H,d), 1.69- 1.87 (2H, m), 2.09 (3H, s), 2.55-2.86 (5H, m), 2.90 (2H, t),3.10-3.23 (1H, m), 3.46-3.71 (3H, m), 4.37 (2H, t), 4.44 (1H, t), 4.55(1H, t), 5.12 (1H, s), 5.37 (1H, t), 6.92-7.06 (2H, m), 7.21 (1H, d),7.43 (1H, d), 8.51 (1H, s), 10.46 (1H, s). (1 exchangeable proton notobserved.) 492 116 

3-((1R,3R)-1- (6-fluoro-3-(2- ((3- fluoropropyl) amino)ethoxy)- 2-methylphenyl)- 3-methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4- b]indol-2-yl)propanoic acid 1H NMR (300 MHz, DMSO-d₆, 27° C.) 1.02 (3 H, d), 1.66-1.89 (5H, m), 1.96- 2.17 (1H, m), 2.18- 2.32 (1H, m), 2.53- 2.70 (4H,m), 2.71- 2.93 (3H, m), 2.94- 3.05 (1H, m), 3.55- 3.66 (1H, m), 3.86-4.06 (2H, m), 4.38 (1H, t), 4.54 (1H, t), 5.22 (1H, s), 6.87- 7.11 (4H,m), 7.13- 7.25 (1H, m), 7.34- 7.44 (1H, m), 10.26 486 (1H, s). (2exchangeable protons not observed.) 118 

2,2-difluoro-3- ((1R,3R)-1-(6- fluoro-3-(2- ((3- fluoropropyl)amino)ethoxy)- 2- methylphenyl)- 3-methyl- 1,3,4,9- tetrahydro-2H-pyrido[3,4- b]indol-2- yl)propanoic acid ¹H NMR (300 MHz, DMSO-d₆, 27°C.) 1.04 (3H, d), 1.78 (3H, s), 1.90-2.10 (2H, m), 2.63 (1H, br d),2.77-3.05 (6H, m), 3.65-3.76 (1H, m), 4.24-4.36 (1H, m), 4.37-4.58 (3H,m), 5.22 (1H, s), 6.89- 7.04 (4H, m), 7.15- 7.21 (1H, m), 7.35- 7.43(1H, m), 10.32 (1H, s). (Three hydrogens no observed, at least one 522multiplet obscured by water peak.) 119 

3-((1R,3R)-1- (6-fluoro-3-(2- ((3- fluoropropyl) amino)ethoxy)- 2-methylphenyl)- 3-methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2-yl)- 2,2- dimethyl- propanoic acid ¹H NMR (500 MHz, CDCl₃, 27°C.) 0.87 (3H, s), 1.19 (3H, d), 1.23 (3H, s), 1.82- 2.03 (3H, m), 2.67-2.81 (5H, m), 2.85 (2H, t), 2.98 (1H, d), 3.13 (1H, s), 3.25 (1H, d),3.61 (1H, s), 4.12 (1H, ddd), 4.28 (1H, s), 4.45 (1H, t), 4.55 (1H, t),5.38 (1H, s), 6.82 (1H, dd), 6.95 (lH,t), 7.07-7.15 (2H, m), 7.16-7.21(1H, m), 514 7.30 (1H, s), 7.48- 7.53 (1H, m). (2 exchangeables notobserved) 120 

1-((R,3R)-1- (6-fluoro-3-(2- ((3- fluoropropyl) amino)ethoxy)- 2-methylphenyl)- 3-methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4- b]indol-2-yl)methyl) cyclobutane-1- carboxylic acid 1H NMR (500 MHz, CDCl₃) 1.25(d, 3H), 1.70 (m, 2H), 1.76 (s, 3H), 1.86 (m, 2H), 1.93-2.05 (m, 2H),2.10-2.30 (m, 2H), 2.57 (m, 1H), 2.72 (d, 1H), 2.76 (d, 1H), 3.01 (m,1H), 3.06 (d, 1H), 3.16 (m, 2H), 3 .21 (m, 1H), 3.63 (m, 1H), 4.15 (dt,2H), 4.49 (dt, 2H), 5.36 (s, 1H), 6.79 (dd, 1H), 6.93 (m, 1H), 7.11 (m,526 2H), 7.19 (d, 1H), 7.49 (d, 1H), 7.63 (s, 1H), 8.26 (s, 1H). (1exchangeable not observed). 122 

(S)-3-((1R,3R)- 3-ethyl-1-(6- fluoro-3-(2- ((3- fluoropropyl)amino)ethoxy)- 2- methylphenyl)- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2-yl)- 2- methylpropanoic acid ¹H NMR (300 MHz, DMSO-d₆, 27° C.)0.77 (3H, d), 0.90 (3H, t), 1.19-1.34 (1H, m), 1.65-1.93 (6H, m),2.14-2.31 (2H, m), 2.69-3.09 (8H, m), 3.16 (1H, br d), 3.95-4.09 (2H,m), 4.47 (2H, dt), 5.27 (1H, s), 6.90- 7.08 (4H, m), 7.14- 7.19 (1H, m),7.38- 7.43 (1H, m), 8.45 (1H, br s), 10.29 (1H, s). 514 123 

(R)-3- ((1R,3R)-1-(3- (2-((3,3- difluoropropyl) amino)ethoxy)-6-fluoro-2- methylphenyl)- 3-methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2-yl)- 2- methylpropanoic acid ¹H NMR (500 MHz, CDCl₃, 27° C.)1.06 (3H, d), 1.20 (3H, d), 1.80 (3H, s), 2.06 (2H, ddt), 2.49-2.63 (1H,m), 2.62-2.74 (1H, m), 2.77-2.86 (2H, m), 2.89 (2H, t), 3.03 (2H, t),3.17- 3.29 (1H, m), 3.84 (1H, p), 4.06 (2H, s), 5.35 (1H, s), 5.88 (1H,t), 6.79 (1H, dd), 6.90 (1H, d), 7.05-7.14 (2H, m), 7.18 (1H, tt), 7.50518 (1H, dd), 7.62 (1H, s). (2 exchangeables not observed). 125 

(S)-3-((1R,3R)- 1-(2- (difluoromethyl)- 6-fluoro-3- (2-((3-fluoropropyl) amino)ethoxy) phenyl)-3- methyl- 1,3,4,9- tetrahydro-2H-pyrido[3,4- b]indol-2-yl)- 2- methylpropanoic acid 1H NMR (500 MHz,CDCl₃, 27° C.) 0.94 (3H, d), 1.18 (3H, d), 1.92 (2H, ddt), 2.79 (2H,dd), 2.86 (3H, t), 3.00-3.12 (3H, m), 3.31 (1H, d), 3.62 (1H, q), 4.14(2H, ddt), 4.50 (1H, t), 4.60 (1H, t), 5.53 (1H, s), 6.95 (1H, dd),7.05-7.25 (4H, m), 7.20 (1H, dd), 7.41 (1H, t), 7.51 (1H, s). (2exchangeables not observed). 536 128 

(S)-3-((1R,3R)- 1-(2,6- dichloro-3-(2- ((3- fluoropropyl) amino)ethoxy)phenyl)-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4- b]indol-2-yl)- 2-methylpropanoic acid ¹HNMR (300 MHz, MeOH-d₄, 27° C.) 0.82-0.94 (3H, m),1.12-1.24 (3H, m), 1.83-2.34 (3H, m), 2.40-2.64 (1H, m), 2.73 (1H, brd), 2.91- 3.10 (3H, m), 3.11- 3.28 (3H, m), 3.65- 3.79 (1H, m), 4.11-4.31 (2H, m), 4.39 (1H, dt), 4.56 (1H, dt), 5.82 (0.5H, s), 5.89 (0.5H,s), 6.92- 7.02 (2H, m), 7.06- 536 7.19 (2H, m), 7.20- 7.26 (0.5H, m),7.37- 7.42 (1H, m), 7.47 (0.5H, d). (One hydrogen not observed.) 129 

3-(1R,3R)-1- (2,6-dichloro- 3-(2-((3- fluoropropyl) amino)ethoxy)phenyl)-6- fluoro-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2-yl)- 2- methylpropanoic acid ¹H NMR (600 MHz, MeOH-d₄, 27° C.)0.99-1.09 (3H, m), 1.17-1.28 (3H, m), 1.94-2.16 (2H, m), 2.34-2.59 (1H,m), 2.60-2.63 (0.4H, m), 2.66-2.81 (1.6H, m), 2.82- 3.28 (5H, m), 3.32-3.47 (1H, m), 3.85- 3.95 (1H, m), 4.24- 4.63 (4H, m), 5.80- 5.85 (0.6H,m), 5.94- 5.99 (0.4H, m), 6.73-6.79 (1H, m), 7.06 (1H, br d), 7.10- 7.21(2H, m), 7.23- 7.28 (0.4H, m), 7.46- 7.52 (0.6H, m), 554 8.53 (3H, brs). (Three hydrogens and formic acid OH signals not observed.) 130 

3-((1R,3R)-1- (2,6-dichloro- 3-(2-((3- fluoropropyl) amino)ethoxy)phenyl)-6- fluoro-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2-yl)- 2- methylpropanoic acid ¹H NMR (600 MHz, MeOH-d₄, 27° C.)0.81-0.94 (3H, m), 1.12-1.19 (3H, m), 1.90-2.34 (3H, m), 2.37-2.46(0.4H, m), 2.47-2.57 (0.6H, m), 2.65- 2.72 (1H, m), 3.03 (1H, td),3.08-3.17 (2H, m), 3.22-3.28 (1H, m), 3.32-3.39 (2H, m), 3.40-3.51 (1H,m), 3.65-3.76 (1H, m), 4.22-4.32 (1H, m), 4.37 (1H, br s), 4.40-4.46(0.6H, m), 4.47-4.52 (0.6H, m), 4.53- 4 56 (0.4H, m), 4.61- 554 4.64(0.4H, m), 5.80 (0.6H, br s), 5.86 (0.4H, s), 6.74 (1H, br t), 7.02-7.06(2H, m), 7.08-7.19 (2H, m), 7.22-7.25 (0.4H, m), 7.43- 7.52 (0.6H, m),8.52 (2H, br s). (Three hydrogens and formic acid OH signals notobserved.) 131 

3-((1R,3R)-1- (2-chloro-6- fluoro-3-(2- ((3- fluoropropyl) amino)ethoxy)phenyl)-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4- b]indol-2-yl)-2,2- dimethylpropanoic acid ¹H NMR (500 MHz, DMSO, 27° C.) 0.83 (3H, s),0.88 (3H, s), 1.06 (3H, d), 1.85 (2H, d), 2.24 (1H, d), 2.75 (2H, s),2.87- 3.07 (5H, m), 3.12 (2H, d), 4.06-4.23 (3H, m), 4.49-4.55 (1H, m),4.56-4.63 (1H, m), 5.40 (1H, s), 6.95-7.05 (2H, m), 7.12 (lH,s), 7.19-7.24 (2H, m), 7.44 (1H, d), 10.43 (1H, s). 534 132

(S)-3-((1R,3R)- 1-(2-(2-((3- fluoropropyl) amino)ethoxy)- 3-methylpyridin- 4-yl)-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2-yl)- 2- methylpropanoic acid ¹H NMR (500 MHz, CDCl₃, 27° C.)1.04 (3H, d), 1.16 (3H, d), 1.92 (2H, ddt), 2.24 (3H, s), 2.44-2.63 (2H,m), 2.67 (1H, dd), 2.85-2.92 (3H, m), 3.00 (1H, d), 3.05 (2H, s), 3.52(1H, q), 4.38-4.47 (3H, m), 4.55 (1H, t), 5.15 (1H, s), 6.49 (1H, s),7.09-7.18 (2H, m), 7.24 (1H, d), 7.53 (1H, d), 7.72 483 (1H, d), 8.40(1H, s). (2 exchangeables not observed) 133 

(S)-3-((1R,3R)- 1-(3-chloro-5- fluoro-2-(2- ((3- fluoropropyl)amino)ethoxy) pyridin-4-yl)-3- methyl- 1,3,4,9- tetrahydro-2H-pyrido[3,4- b]indol-2-yl)- 2- methylpropanoic acid ¹H NMR (500 MHz,CDCl₃, 27° C.) 1.03 (3H, d), 1.23 (3H, d), 1.83-1.98 (2H, m), 2.40 (1H,s), 2.66- 2.76 (2H, m), 2.87 (2H, t), 2.89-2.96 (1H, m), 3.02-3.16 (3H,m), 3.56-3.66 (2H, m), 4.43-4.54 (3H, m), 4.58 (1H, t), 5.58 (1H, s),7.13 (1H, dd), 7.16 (1H, td), 7.24 (1H, d), 7.53 (1H, d), 7.82 521 (1H,s), 7.85 (1H, s). (1 exchangeable not observed). 134 

(S)-3-((R)-1- (6-fluoro-3-(2- ((3- fluoropropyl) amino)ethoxy)- 2-methylphenyl)- 3,3-dimethyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2-yl)- 2- methylpropanoic acid ¹H NMR (500 MHz, CDCl₃, 27° C.)0.87 (3H, d), 1.19-1.28 (4H, m), 1.31-1.41 (1H, m), 1.50 (3H, s), 1.77(3H, s), 1.79- 1.90 (2H, m), 2.78 (3H, q), 2.85 (1H, d), 2.87-2.97 (1H,m), 3.01 (1H, ddd), 3.05- 3.14 (2H, m), 3.95- 4.05 (2H, m), 4.49 (2H,dt), 5.56 (1H, s), 6.85 (1H, dd), 7.00 (1H, t), 7.10- 514 7.18 (2H, m),7.23 (1H, dd), 7.33 (1H, s), 7.47-7.52 (1H, m). (1 exchangeable notobserved.) 135 

(S)-3-((1R,3R)- 1-(6-fluoro-3- ((2-((3- fluoropropyl) amino)ethyl)amino)-2- methylphenyl)- 3-methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2-yl)- 2- methylpropanoic acid ¹H NMR (300 MHz, MeOH-d₄, 27° C.)0.91 (3H, d), 1.38 (3H, br d), 1.69- 2.02 (3H, m), 2.04- 2.25 (2H, m),2.83- 3.14 (3H, m), 3.16- 3.25 (2H, m), 3.26- 3.39 (4H, m, obsc), 3.53(2H, t), 3.80- 4.06 (1H, m), 4.56 (2H, dt), 5.82 (1H, br s), 6.85 (1H,dd), 6.97-7.12 (3H, m), 7.44 (1H, d), 7.46 499 (1H, d). Four hydrogensnot observed. 136 

(S)-3-((1R,3R)- 1-(6-fluoro-3- ((2-((3- fluoropropyl) amino)ethyl)(methyl)amino)- 2- methylphenyl)- 3-methyl- 1,3,4,9- tetrahydro-2H-pyrido[3,4- b]indol-2-yl)- 2- methylpropanoic acid ¹H NMR (300 MHz,MeOH-d₄, 27° C.) 0.81 (3H, d), 1.15 (3H, d), 1.83-2.01 (3H, m), 2.05(3H, s), 2.45 (1H, br dd), 2.55 (3H, s), 2.62- 2.74 (1H, m), 2.87- 3.26(8H, m), 3.74 (1H, br qdd), 4.44 (2H, dt), 5.45 (1H, s), 6.92-7.06 (3H,m), 7.13-7.28 (2H, m), 7.37-7.45 (1H, m). (Three hydrogens notobserved.) 513 137 

(S)-3-((1R,3S)- 3- (difluoromethyl)- 1-(6-fluoro- 3-(2-((3-fluoropropyl) amino)ethoxy)- 2- methylphenyl)- 1,3,4,9- tetrahydro-2H-pyrido[3,4- b]indol-2-yl)- 2- methylpropanoic acid ¹H NMR (300 MHz,DMSO-d₆, 27° C.) 0.72 (3H, d), 1.63- 1.93 (5H, m), 2.00- 2.14 (1H, m),2.41- 2.46 (1H, m), 2.63 (2H, t), 2.80-2.97 (5H, m), 3.60-3.72 (2H, m),3.86-4.05 (3H, m), 4.44 (2H, dt), 5.64 (1H, s), 6.24 (1H, td), 6.90-7.02(4H, m), 7.14-7.20 (1H, m), 7.38-7.44 (1H, m), 8.18 (0.5H, s), 10.41(1H, s). (Formic acid OH not observed.) 536 138 

(S)-3-((1R,3S)- 1-(2-chloro-6- fluoro-3-(2- ((3- fluoropropyl)amino)ethoxy) phenyl)-3- (difluoromethyl)- 1,3,4,9- tetrahydro-2H-pyrido[3,4- b]indol-2-yl)- 2- methylpropanoic acid ¹H NMR (300 MHz,DMSO-d₆, 27° C.) 0.80 (3H, d), 1.76- 1.93 (2H, m), 2.33- 2.48 (2H, m),2.80 (2H, br t), 2.90-2.96 (2H, m), 2.98-3.06 (2H, m), 3.56-3.72 (1H,m), 4.09-4.18 (2H, m), 4.51 (2H, dt), 5.75 (1H, s), 6.20 (1H, br td),6.90- 7.25 (6H, m), 7.41- 7.46 (1H,m), 10.57 (1H, s). (Two hydrogens notobserved.) 556 139 

(S)-3-((1R,3S)- 1-(3-chloro-5- fluoro-2-(2- ((3- fluoropropyl)amino)ethoxy) pyridin-4-yl)-3- (difluoromethyl)- 1,3,4,9- tetrahydro-2H-pyrido[3,4- b]indol-2-yl)- 2- methylpropanoic acid ¹H NMR (300 MHz,DMSO-d₆, 27° C.) 0.83 (3H, d), 1.66- 1.88 (2H, m), 2.35- 2.48 (3H, m),2.68 (2H, t), 2.85-3.00 (4H, m), 3.58-3.71 (1H, m), 4.36 (2H, t), 4.50(2H, dt), 5.74 (1H, s), 6.24 (1H, td), 6.93-7.07 (2H, m), 7.17-7.21 (1H,m), 7.46 (1H, d), 8.07 (1H, s), 10.68 (1H, s). (Two hydrogens notobserved.) 557 140 

(S)-3-((1R,3S)- 1-(6-fluoro-3- (2-((3- fluoropropyl) amino)ethoxy)- 2-methylphenyl)- 3- (trifluoromethyl)- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2-yl)- 2- methylpropanoic acid ¹HNMR (500 MHz, CDCl₃, 27° C.)0.67 (3H, d), 1.86 (3H, s), 1.89-2.02 (2H, m), 2.74 (1H, dd), 2.93 (2H,t), 3.12 (4H, dd), 3.27-3.40 (1H, m), 3.96-4.12 (2H, m), 4.12-4.25 (2H,m), 4.39 (1H, t), 4.48 (1H, t), 5.74 (1H, s), 6.73 (1H, dd), 6.88 (1H,t), 7.02-7.11 (2H, m), 7.12-7.20 (1H, m), 7.40 (1H, s), 7.45 (2H, dd).(1 exchangeable not observed). 554 141 

(S)-3-(1R,3S)- 1-(2-chloro-6- fluoro-3-(2- ((3- fluoropropyl)amino)ethoxy) phenyl)-3- (trifluoromethyl)- 1,3,4,9- tetrahydro-2H-pyrido[3,4- b]indol-2-yl)- 2- methylpropanoic acid ¹HNMR (500 MHz,CDCl₃, 27° C.) 0.80- 0.93 (6H, m), 1.88- 2.02 (2H, m), 2.69 (1H, s),2.86-2.99 (2H, m), 3.03-3.26 (5H, m), 3.27-3.37 (1H, m), 4.05 (1H, s),4.13 (2H, s), 4.38- 4.51 (1H, m), 4.51- 4.60 (1H, m), 4.70 (2H, s), 5.87(1H, s), 6.72-6.80 (2H, m), 7.10 (2H, td), 7.17 (1H, dd), 7.45-7.54 (1H,m), 7.70 (1H, s). 574 142 

(S)-3-((1R,3S)- 1-(3-chloro-5- fluoro-2-(2- ((3- fluoropropyl)amino)ethoxy) pyridin-4-yl)-3- (trifluoromethyl)- 1,3,4,9-tetrahydro-2H- pyrido[3,4- b]indol-2-yl)- 2- methylpropanoic acid ¹H NMR(500 MHz, CDCl₃, 27° C.) 0.92 (3H, d), 1.96 (2H, d), 2.34 (1H, d), 2.59(1H, s), 2.95 (2H, s), 3.16 (4H, d), 3.45 (1H, s), 4.01 (1H, s), 4.41(2H, s), 4.50 (1H, s), 4.58 (1H, s), 5.82 (1H, s), 6.55- 6.66 (2H, m),7.10 (2H, dq), 7.18 (1H, d), 7.49 (1H, d), 7.61 (1H, s), 7.98 (1H, s).575 144 

(S)-3-((1R,3R)- 1-(2,6- difluoro-3-(2- ((3- fluoropropyl) (methyl)amino)ethoxy)phenyl)- 3-methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2-yl)- 2- methylpropanoic acid ¹H NMR (300 MHz, DMSO-d₆, 27° C.)0.83 (3H, d), 1.00- 1.06 (3H, m), 1.65- 1.84 (2H, m), 2.15- 2.28 (4H,m), 2.44 (2H, t), 2.57 (1H, br dd), 2.68 (2H, t), 2.77-2.97 (2H, m),4.05 (2H, t), 4.44 (2H, dt), 5.15 (1H, s), 6.90-7.02 (3H, m), 7.11-7.22(2H, m), 7.35-7.43 (1H, m), 10.56 (1H, s). 518 (One hydrogen obscured bywater, two hydrogens not observed.) 146 

(S)-3-((1R,3R)- 6-fluoro-1-(6- fluoro-3-(2- ((3- fluoropropyl)(methyl)amino) ethoxy)-2- methylphenyl)- 3-methyl- 1,3,4,9-tetrahydro-2H- pyrido[3,4- b]indol-2-yl)- 2- methylpropanoic acid ¹H NMR(500 MHz, CDCl₃, 27° C.) 0.89 (3H, d), 1.25 (3H, d), 1.82 (2H, dd),1.86- 1.93 (3H, m), 2.32 (3H, s), 2.54-2.62 (2H, m), 2.63-2.86 (5H, m),2.89 (1H, dd), 3.23 (1H, d), 3.54-3.65 (1H, m), 4.01 (2H, t), 4.41 (1H,t), 4.51 (1H, t), 5.51 (1H, s), 6.76- 6.91 (2H, m), 6.94 (1H, t),7.07-7.19 (2H, m), 7.52 (1H, s). 532 147 

(S)-3-((1R,3R)- 1-(6-fluoro-3- ((2-((3- fluoropropyl) (methyl)amino)ethyl)(methyl) amino)-2- methylphenyl)- 3-methyl- 1,3,4,9-tetrahydro-2H- pyrido[3,4- b]indol-2-yl)- 2- methylpropanoic acid ¹H NMR(300 MHz, MeOH-d₄, 27° C.) 0.84 (3H, d), 1.15- 1.25 (3H, m), 1.75- 2.08(6H, m), 2.40 (3H, s), 2.54-2.58 (3H, m), 2.58-2.66 (1H, m), 2.66-2.80(5H, m), 2.95-3.23 (4H, m), 3.68-3.81 (1H, m), 4.40 (2H, dt), 5.06 (1H,s), 5.53 (1H, br s), 6.94- 7.06 (3H, m), 7.13- 7.28 (2H, m), 7.33- 7.51(1H, m). 527 (Indole NH not observed.) 148 

(S)-3-((1R,3R)- 1-(2- (difluoromethyl)- 6-fluoro-3- (2-((3-fluoropropyl) (methyl)amino) ethoxy)phenyl)- 3-methyl- 1,3,4,9-tetrahydro-2H- pyrido[3,4- b]indol-2-yl)- 2- methylpropanoic acid ¹HNMR(500 MHz, CDCl₃, 27° C.) 0.93 (3H, d), 1.21 (3H, d), 1.85-1.98 (2H, m),2.37 (3H, s), 2.63 (2H, s), 2.73-2.81 (3H, m), 2.88 (2H, s), 3.17 (1H,s), 3.33- 3.41 (1H, m), 3.58- 3.67 (1H, m), 4.17 (2H, s), 4.54 (2H, dt),5.60 (1H, s), 6.93- 7.01 (1H, m), 7.06- 7.15 (4H, m), 7.18- 7.22 (1H,m), 7.39 (1H, s), 7.50-7.53 550 (1H, m). (1 exchangeable not observed)149 

(S)-3-((1R,3S)- 1-(6-fluoro-3- (2-((3- fluoropropyl) (methyl)amino)ethoxy)-2- methylphenyl)- 3- (trifluoromethyl)- 1,3,4,9- tetrahydro-2H-pyrido[3,4- b]indol-2-yl)- 2- methylpropanoic acid ¹HNMR (500 MHz,CDCl₃, 27° C.) 0.79 (3H, d), 1.88-1.95 (2H, m), 1.98-2.06 (1H, m),2.34-2.41 (4H, m), 2.64-2.69 (2H, m), 2.80-2.89 (4H, m), 3.13 (1H, d),3.22 (1H, dd), 3.29-3.4 (2H, m), 4.00-4.16 (3H, m), 4.45 (2H, dt), 5.78(1H, s), 6.81 (1H, dd), 6.93 (1H, t), 7.07-7.13 (2H, m), 7.17-7.19 (1H,m), 568 7.33 (1H, s), 7.45- 7.49 (1H, m). (1 exchangeable not observed)150 

(S)-3-((1R,3R)- 1-(6-fluoro-3- (2-((3- fluoropropyl) (methyl- d3)amino)ethoxy)-2- methylphenyl)- 3-methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2-yl)- 2- methylpropanoic acid ¹H NMR (500 MHz, CDCl₃, 27° C.)0.90 (3H, d), 1.25 (3H, d), 1.70-1.96 (5H, m), 2.56 (2H, t), 2.70- 2.82(5H, m), 2.90 (1H, dd), 3.20-3.32 (1H, m), 3.56-3.67 (1H, m), 3.99 (2H,t), 4.42 (1H, t), 4.52 (1H, t), 5.53 (1H, s), 6.83 (1H, dd), 6.94 (1H,t), 7.06-7.18 (2H, m), 7.22 (1H, dd), 7.46 (1H, s), 7.51 (1H, dd). 517151 

(R)-3- ((1R,3R)-1-(6- fluoro-3-(2- ((3- fluoropropyl) (methyl)amino)ethoxy)-2- methylphenyl)- 3-methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4-b]indol-2-yl)- 2- methylpropanoic acid ¹H NMR (500 MHz, CDCl₃, 27° C.)1.09 (3H, d), 1.21 (3H, d), 1.75-1.90 (5H, m), 2.32 (3H, s), 2.53- 2.61(3H, m), 2.68 (1H, s), 2.81 (4H, td), 3.20-3.31 (1H, m), 3.84 (1H, p),4.02 (2H, ddq), 4.41 (1H, t), 4.51 (1H, t), 5.34 (1H, s), 6.82 (1H, dd),6.92 (1H, t), 7.07-7.16 (2H, m), 7.17-7.22 (1H, m), 7.41 (1H, s), 7.50(1H, dd). 514 153 

(R)-3- ((1R,3R)-1-(5- fluoro-2-(2- ((3- fluoropropyl) (methyl-d3)amino)ethoxy)- 3- methylpyridin- 4-yl)-3- methyl- 1,3,4,9-tetrahydro-2H- pyrido[3,4- b]indol-2-yl)- 2- methylpropanoic acid ¹H NMR(500 MHz, CDCl₃, 27° C.) 1.04 (3H, d), 1.15 (3H, d), 1.78-1.94 (5H, m),2.46-2.56 (1H, m), 2.56-2.73 (4H, m), 2.78 (1H, d), 3.01 (1H, ddd), 3.20(1H, ddd), 3.70 (2H, q), 4.26 (1H, ddd), 4.39 (1H, t), 4.49 (1H, t),4.66-4.77 (1H, m), 5.26 (1H, s), 7.12 (2H, dtd), 7.22 (1H, dd), 7.51(2H, dd), 7.89 (1H, s). 518 154 

N-(2-(2,4- difluoro-3- ((1R,3R)-2-((3- fluorooxetan- 3-yl)methyl)-3-methyl- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1- yl)phenoxy)ethyl)-3-fluoro-N- methylpropan- 1-amine ¹H NMR (300 MHz, DMSO-d₆, 27°C.) 1.10 (3H, d), 1.66- 1.84 (2H, m), 2.21 (3H, s), 2.45 (2H, t), 2.58(1H, dd), 2.67 (2H, t), 2.70-2.86 (2H, m), 3.15-3.30 (1H, m), 3.33-3.42(1H, m), 4.05 (2H, t), 4.22-4.58 (6H, m), 5.26 (1H, s), 6.90- 7.02 (3H,m), 7.11- 7.22 (2H, m), 7.40 (1H, d), 10.59 (1H, s). 520

The above description of illustrative embodiments is intended only toacquaint others skilled in the art with the Applicant's specification,its principles, and its practical application so that others skilled inthe art may readily adapt and apply the specification in its numerousforms, as they may be best suited to the requirements of a particularuse. This description and its specific examples, while indicatingembodiments of this specification, are intended for purposes ofillustration only. This specification, therefore, is not limited to theillustrative embodiments described in this specification, and may bevariously modified. In addition, it is to be appreciated that variousfeatures of the specification that are, for clarity reasons, describedin the context of separate embodiments, also may be combined to form asingle embodiment. Conversely, various features of the specificationthat are, for brevity reasons, described in the context of a singleembodiment, also may be combined to form sub-combinations thereof.

1-14. (canceled)
 15. A compound, or a pharmaceutically acceptable saltthereof, wherein the compound is(S)-3-((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid, which compound has the following structure:


16. A pharmaceutical composition, which comprises the compound accordingto claim 15, or a pharmaceutically acceptable salt thereof, inassociation with a pharmaceutically-acceptable excipient.
 17. Acompound, wherein the compound is(S)-3-((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid.
 18. A pharmaceutical composition, which comprises the compoundaccording to claim 17, in association with a pharmaceutically-acceptableexcipient.
 19. A pharmaceutically acceptable salt of(S)-3-((1R,3R)-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid.
 20. A pharmaceutical composition, which comprises the saltaccording to claim 19, in association with a pharmaceutically-acceptableexcipient.
 21. A compound, or a pharmaceutically acceptable saltthereof, wherein the compound is(S)-3-((1R,3R)-6-fluoro-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid, which compound has the following structure:


22. A pharmaceutical composition, which comprises the compound accordingto claim 21, or a pharmaceutically acceptable salt thereof, inassociation with a pharmaceutically-acceptable excipient.
 23. Acompound, wherein the compound is(S)-3-((1R,3R)-6-fluoro-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid.
 24. A pharmaceutical composition, which comprises the compoundaccording to claim 23, in association with a pharmaceutically-acceptableexcipient.
 25. A pharmaceutically acceptable salt of(S)-3-((1R,3R)-6-fluoro-1-(6-fluoro-3-(2-((3-fluoropropyl)amino)ethoxy)-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid.
 26. A pharmaceutical composition, which comprises the saltaccording to claim 25, in association with a pharmaceutically-acceptableexcipient.
 27. A compound, or a pharmaceutically acceptable saltthereof, wherein the compound is(S)-3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid, which compound has the following structure:


28. A pharmaceutical composition, which comprises the compound accordingto claim 27, or a pharmaceutically acceptable salt thereof, inassociation with a pharmaceutically-acceptable excipient.
 29. Acompound, wherein the compound is(S)-3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid.
 30. A pharmaceutical composition, which comprises the compoundaccording to claim 29, in association with a pharmaceutically-acceptableexcipient.
 31. A pharmaceutically acceptable salt of(S)-3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid.
 32. A pharmaceutical composition, which comprises the saltaccording to claim 31, in association with a pharmaceutically-acceptableexcipient.
 33. A compound, or a pharmaceutically acceptable saltthereof, wherein the compound is(R)-3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid, which compound has the following structure:


34. A pharmaceutical composition, which comprises the compound accordingto claim 33, or a pharmaceutically acceptable salt thereof, inassociation with a pharmaceutically-acceptable excipient.
 35. Acompound, wherein the compound is(R)-3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid.
 36. A pharmaceutical composition, which comprises the compoundaccording to claim 35, in association with a pharmaceutically-acceptableexcipient.
 37. A pharmaceutically acceptable salt of(R)-3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-methylpropanoicacid.
 38. A pharmaceutical composition, which comprises the saltaccording to claim 37, in association with a pharmaceutically-acceptableexcipient.